Recent Journal Articles: Nephrology and Urology -- Neurotransmitter.net

Recent Articles in Journal of the American Society of Nephrology: JASN

Proceedings of the 5th International Conference on Hypertension and the Kidney, February 2006, Madrid, Spain.
J Am Soc Nephrol. 2006 Dec;17(12 Suppl 3):S157-303. [Abstract]

Volkova N, McClellan W, Klein M, Flanders D, Kleinbaum D, Soucie JM, Presley R
Neighborhood Poverty and Racial Differences in ESRD Incidence.
J Am Soc Nephrol. 2007 Dec 5;
Poverty is associated with increased risk of ESRD, but its contribution to observed racial differences in disease incidence is not well-defined. To explore the contribution of neighborhood poverty to racial disparity in ESRD incidence, we analyzed a combination of US Census and ESRD Network 6 data comprising 34,767 patients that initiated dialysis in Georgia, North Carolina, or South Carolina between January 1998 and December 2002. Census tracts were used as the geographic units of analysis, and the proportion of the census tract population living below the poverty level was our measure of neighborhood poverty. Incident ESRD rates were modeled using two-level Poisson regression, where race, age and gender were individual covariates (level 1), and census tract poverty was a neighborhood covariate (level 2). Neighborhood poverty was strongly associated with higher ESRD incidence for both blacks and whites. Increasing poverty was associated with a greater disparity in ESRD rates between blacks and whites, with the former at greater risk. This raises the possibility that blacks may suffer more from lower socioeconomic conditions than whites. The disparity persisted across all poverty levels. The reasons for increasingly higher ESRD incidence among US blacks as neighborhood poverty increases remain to be explained. [Abstract]

Li C, Wang W, Summer SN, Westfall TD, Brooks DP, Falk S, Schrier RW
Molecular Mechanisms of Antidiuretic Effect of Oxytocin.
J Am Soc Nephrol. 2007 Dec 5;
Oxytocin is known to have an antidiuretic effect, but the mechanisms underlying this effect are not completely understood. We infused oxytocin by osmotic minipump into vasopressin-deficient Brattleboro rats for five days and observed marked antidiuresis, increased urine osmolality, and increased solute-free water reabsorption. Administration of oxytocin also significantly increased the protein levels of aquaporin-2 (AQP2), phosphorylated AQP2 (p-AQP2), and AQP3 in the inner medulla and in the outer medulla plus cortex. Immunohistochemistry demonstrated increased AQP2 and p-AQP2 expression and trafficking to the apical plasma membrane of principal cells in the collecting duct, and increased AQP3 expression in the basolateral membrane. These oxytocin-induced effects were blocked by treatment with the vasopressin V2 receptor antagonist SR121463B, but not by treatment with the oxytocin receptor antagonist GW796679X. We conclude that vasopressin V2 receptors mediate the antidiuretic effects of oxytocin, including increased expression and apical trafficking of AQP2, p-AQP2, and increased AQP3 protein expression. [Abstract]

Liu F, Brezniceanu ML, Wei CC, Ch�nier I, Sachetelli S, Zhang SL, Filep JG, Ingelfinger JR, Chan JS
Overexpression of Angiotensinogen Increases Tubular Apoptosis in Diabetes.
J Am Soc Nephrol. 2007 Dec 5;
The intrarenal renin-angiotensin system (RAS) plays an important role in the progression of diabetic nephropathy. We have previously reported that mice overexpressing angiotensinogen in renal proximal tubular cells (RPTC) develop hypertension, albuminuria, and renal injury. Here, we investigated whether activation of the intrarenal RAS contributes to apoptosis of RPTC in diabetes. Induction of diabetes with streptozotocin in these transgenic mice led to significant increases in BP, albuminuria, RPTC apoptosis, and proapoptotic gene expression compared with diabetic nontransgenic littermates. Insulin and/or RAS blockers markedly attenuated these changes. Hydralazine prevented hypertension but not albuminuria, RPTC apoptosis, or proapoptotic gene expression. In vitro, high-glucose medium significantly increased apoptosis and caspase-3 activity in rat immortalized RPTC overexpressing angiotensinogen compared with control cells, and these changes were prevented by insulin and/or RAS blockers. In conclusion, intrarenal RAS activation and high glucose may act in concert to increase tubular apoptosis in diabetes, independent of systemic hypertension. [Abstract]

Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM
Low Birth Weight Increases Risk for End-Stage Renal Disease.
J Am Soc Nephrol. 2007 Dec 5;
Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001). Births with a weight for gestational age <10th percentile had an RR of 1.5 (95% confidence interval 1.2 to 1.9; P = 0.002). These associations were virtually identical after adjustment for birth-related confounders such as congenital malformations, multiple delivery, maternal age at birth, and maternal preeclampsia. Low birth weight was more strongly associated with development of ESRD during the first 14 years of life than after age 15. Low birth weight and low birth weight for gestational age were similarly associated with multiple causes of ESRD. In conclusion, in this cohort study with a maximum follow-up of 38 years, low birth weight and intrauterine growth restriction were associated with increased risk for ESRD. [Abstract]

Schneider CA, Ferrannini E, Defronzo R, Schernthaner G, Yates J, Erdmann E
Effect of Pioglitazone on Cardiovascular Outcome in Diabetes and Chronic Kidney Disease.
J Am Soc Nephrol. 2007 Dec 5;
Patients with diabetes and chronic kidney disease (CKD) are at particularly high risk for cardiovascular disease (CVD). This post hoc analysis from the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive) investigated the relationship between CKD and incident CVD in a population of patients with diabetes and documented macrovascular disease, as well as the effects of pioglitazone treatment on recurrent CVD. CKD, defined as an estimated GFR <60 ml/min per 1.73m(2), was present in 597 (11.6%) of 5154 patients. More patients with CKD reached the primary composite end point (all-cause mortality, myocardial infarction (MI), stroke, acute coronary syndrome, coronary/carotid arterial intervention, leg revascularization, or amputation above the ankle) than patients without CKD (27.5 versus 19.6%; P < 0.0001). Patients with CKD were also more likely to reach a secondary composite end point (all-cause mortality, MI, and stroke). Patients who had CKD and were treated with pioglitazone were less likely to reach the secondary end point (hazard ratio 0.66; 95% confidence interval 0.45 to 0.98), but this association was not observed among those with better renal function. In addition, there was a greater decline in estimated GFR with pioglitazone (between-group difference 0.8 ml/min per 1.73 m(2)/yr) than with placebo. In conclusion, CKD is an independent risk factor for cardiovascular events and death among patients with diabetes and preexisting macrovascular disease. Patients who had CKD and were treated with pioglitazone were less likely to reach a composite end point of all-cause death, MI, and stroke, independent of the severity of renal impairment. [Abstract]

Pavlakis M
Resolved: in minimizing kidney transplant immunosuppression, steroids should go before calcineurin inhibitors: con.
J Am Soc Nephrol. 2007 Dec;18(12):3028-30. [Abstract]

Tu X, Chen X, Xie Y, Shi S, Wang J, Chen Y, Li J
Anti-inflammatory Renoprotective Effect of Clopidogrel and Irbesartan in Chronic Renal Injury.
J Am Soc Nephrol. 2007 Nov 28;
Recent evidence suggests that platelet activation and angiotensin II may each contribute to glomerular inflammation and fibrosis. Clopidogrel inhibits platelet activation and may also reduce inflammation. This study investigated the anti-inflammatory and renoprotective effects of clopidogrel and irbesartan in the five-sixths nephrectomy rat model of chronic kidney disease. After 8 wk of treatment, 24-h proteinuria, serum creatinine, and histologic scores of glomerular sclerosis and tubulointerstitial damage were significantly lower in treated compared with untreated rats. Clopidogrel/irbesartan combination therapy had greater effects than either drug alone. Rats that underwent five-sixths nephrectomy had higher markers of platelet activation (plasma GMP-140 and renal cortical fibrin deposition) than sham-operated rats, and clopidogrel attenuated these effects. Clopidogrel and irbesartan similarly reduced the accumulation of ED-1-expressing macrophages in the cortical glomeruli and the interstitium. Combination therapy almost completely abolished macrophage infiltration and attenuated the expression of monocyte chemoattractant protein-1, intercellular adhesion molecule-1, TGF-beta1, and connective tissue growth factor. In conclusion, combination treatment with clopidogrel and irbesartan, more so than either alone, decreases early renal injury induced by five-sixths nephrectomy by inhibiting renal inflammation. [Abstract]

Awad AS, Rouse M, Liu L, Vergis AL, Rosin DL, Linden J, Sedor JR, Okusa MD
Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes.
J Am Soc Nephrol. 2007 Nov 28;
Adenosine 2A receptor (A2AR) activation was recently shown to be renoprotective in diabetic nephropathy. A2AR are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein alpha-actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A2AR agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A2AR antagonist ZM241385 reversed the effects of ATL313. In vitro, A2AR mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A2AR-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleoside-induced injury in vitro. ATL313 was ineffective, however, in the presence of the A2AR antagonist and in A2AR-deficient podocytes. It was concluded that A2AR activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton. [Abstract]

Alpers CE, Kowalewska J
Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy.
J Am Soc Nephrol. 2007 Nov 28;
Fibrillary glomerulonephritis is a now widely recognized diagnostic entity, occurring in approximately 1% of native kidney biopsies in several large biopsy series obtained from Western countries. The distinctive features are infiltration of glomerular structures by randomly arranged fibrils similar in appearance but larger than amyloid fibrils and the lack of staining with histochemical dyes typically reactive with amyloid. It is widely but not universally recognized to be distinct from immunotactoid glomerulopathy, an entity characterized by glomerular deposits of immunoglobulin with substructural organization as microtubules and with clinical associations with lymphoplasmacytic disorders. The pathophysiologic basis for organization of the glomerular deposits as fibrils or microtubules in these entities remains obscure. [Abstract]

Bloom RD, Reese PP
Chronic kidney disease after nonrenal solid-organ transplantation.
J Am Soc Nephrol. 2007 Dec;18(12):3031-41.
Chronic kidney disease (CKD) is a common complication after nonrenal solid-organ transplantation. The risk for CKD is influenced by many factors, some of which have a direct impact on how such patients are treated in the pre-, peri-, and posttransplantation settings. This review describes hazards for acute and chronic kidney injury, with particular emphasis on calcineurin inhibitor-mediated nephrotoxicity. Rather than a detailed description of management issues that are common to the general CKD population, highlighted are aspects that are more specific to nonrenal solid-organ transplant recipients with a focus on liver, heart, and lung recipients. Strategies to minimize nephrotoxic insults and retard progressive renal injury are discussed, as are issues that are pertinent to dialysis and transplantation. Finally, future approaches to prevent and treat CKD without compromising function of the transplanted organ are addressed. [Abstract]

Bustamante M, Hasler U, Leroy V, de Seigneux S, Dimitrov M, Mordasini D, Rousselot M, Martin PY, F�raille E
Calcium-sensing Receptor Attenuates AVP-induced Aquaporin-2 Expression via a Calmodulin-dependent Mechanism.
J Am Soc Nephrol. 2007 Nov 21;
Recent evidence suggests that arginine vasopressin (AVP)-dependent aquaporin-2 expression is modulated by the extracellular calcium-sensing receptor (CaSR) in principal cells of the collecting duct, but the signaling pathways mediating this effect are unknown. Using a mouse cortical collecting duct cell line (mpkCCDcl4), we found that increasing the concentration of apical extracellular calcium or treating with the CaSR agonists neomycin or Gd(3+) attenuated AVP-dependent accumulation of aquaporin-2 mRNA and protein; CaSR gene-silencing prevented this effect. Calcium reduced the AVP-induced accumulation of cAMP, but this did not occur by increased degradation of cAMP by phosphodiesterases or by direct inhibition of adenylate cyclase. Notably, the effect of extracellular calcium on AVP-dependent aquaporin-2 expression was prevented by inhibition of calmodulin. In summary, our results show that high concentrations of extracellular calcium attenuate AVP-induced aquaporin-2 expression by activating the CaSR and reducing coupling efficiency between V2 receptor and adenylate cyclase via a calmodulin-dependent mechanism in cultured cortical collecting duct cells. [Abstract]

Balazs Z, Schweizer RA, Frey FJ, Rohner-Jeanrenaud F, Odermatt A
DHEA Induces 11{beta}-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins.
J Am Soc Nephrol. 2007 Nov 21; [Abstract]

Wattanakit K, Cushman M, Stehman-Breen C, Heckbert SR, Folsom AR
Chronic Kidney Disease Increases Risk for Venous Thromboembolism.
J Am Soc Nephrol. 2007 Nov 21;
Chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease morbidity and mortality, but its association with incident venous thromboembolism (VTE) in non-dialysis-dependent patients has not been evaluated in a community-based population. With the use of data from the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, 19,073 middle-aged and elderly adults were categorized on the basis of estimated GFR, and cystatin C (available in 4734 participants) was divided into quintiles. During a mean follow-up time of 11.8 yr, 413 participants developed VTE. Compared with participants with normal kidney function, relative risk for VTE was 1.28 (95% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95% CI 1.47 to 2.96) for those with stage 3/4 CKD, when adjusted for age, gender, race, and center. After additional adjustment for cardiovascular disease risk factors, an increased risk for VTE was still observed in participants with stage 3/4 CKD, with a multivariable adjusted relative risk of 1.71 (95% CI 1.18 to 2.49). There was no significant association between cystatin C and VTE. In conclusion, middle-aged and elderly patients with CKD (stages 3 through 4) are at increased risk for incident VTE, suggesting that VTE prophylaxis may be particularly important in this population. [Abstract]

Bailey MA, Paterson JM, Hadoke PW, Wrobel N, Bellamy CO, Brownstein DG, Seckl JR, Mullins JJ
A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess.
J Am Soc Nephrol. 2007 Nov 21;
The syndrome of apparent mineralocorticoid excess arises from nonfunctional mutations in 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), an enzyme that inactivates cortisol and confers aldosterone specificity on the mineralocorticoid receptor. Loss of 11betaHSD2 permits glucocorticoids to activate the mineralocorticoid receptor, and the hypertension in the syndrome is presumed to arise from volume expansion secondary to renal sodium retention. An 11betaHSD2 null mouse was generated on an inbred C57BL/6J genetic background, allowing survival to adulthood. 11betaHSD2(-/-) mice had BP approximately 20 mmHg higher on average compared with wild-type mice but were volume contracted, not volume expanded as expected. Initially, impaired sodium excretion associated with increased activity of the epithelial sodium channel was observed. By 80 days of age, however, channel activity was abolished and 11betaHSD2(-/-) mice lost salt. Despite the natriuresis, hypertension remained but was not attributable to intrinsic vascular dysfunction. Instead, urinary catecholamine levels in 11betaHSD2(-/-) mice were double those in wild-type mice, and alpha1-adrenergic receptor blockade rescued the hypertensive phenotype, suggesting that vasoconstriction contributes to the sustained hypertension in this model. In summary, it is proposed that renal sodium retention remains a key event in apparent mineralocorticoid excess but that the accompanying hypertension changes from a renal to a vascular etiology over time. [Abstract]

He L, Sun Y, Takemoto M, Norlin J, Tryggvason K, Samuelsson T, Betsholtz C
The Glomerular Transcriptome and a Predicted Protein Protein Interaction Network.
J Am Soc Nephrol. 2007 Nov 21;
To increase our understanding of the molecular composition of the kidney glomerulus, we performed a meta-analysis of available glomerular transcriptional profiles made from mouse and man using five different methodologies. We generated a combined catalogue of glomerulus-enriched genes that emerged from these different sources and then used this to construct a predicted protein-protein interaction network in the glomerulus (GlomNet). The combined glomerulus-enriched gene catalogue provides the most comprehensive picture of the molecular composition of the glomerulus currently available, and GlomNet contributes an integrative systems biology approach to the understanding of glomerular signaling networks that operate during development, function, and disease. [Abstract]

Wang X, Wu Y, Ward CJ, Harris PC, Torres VE
Vasopressin Directly Regulates Cyst Growth in Polycystic Kidney Disease.
J Am Soc Nephrol. 2007 Nov 21;
The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD. [Abstract]

Grantham JJ
Therapy for Polycystic Kidney Disease? It's Water, Stupid!
J Am Soc Nephrol. 2007 Nov 21; [Abstract]

Baud L, Letavernier E
PPARalpha contributes to tubular protection.
J Am Soc Nephrol. 2007 Dec;18(12):3017-8. [Abstract]

Markowitz GS, Radhakrishnan J, D'Agati VD
Towards the incidence of acute phosphate nephropathy.
J Am Soc Nephrol. 2007 Dec;18(12):3020-2. [Abstract]

Rosenberg ME, Gupta S
Stem cells and the kidney: where do we go from here?
J Am Soc Nephrol. 2007 Dec;18(12):3018-20. [Abstract]

Novak JE, Szczech LA
Feast and Famine: Epidemiology and Clinical Trials in Chronic Kidney Disease.
J Am Soc Nephrol. 2007 Nov 14; [Abstract]

Matas AJ
Resolved: in minimizing kidney transplant immunosuppression, steroids should go before calcineurin inhibitors: pro.
J Am Soc Nephrol. 2007 Dec;18(12):3026-8.
Without direct comparison or randomized controlled trials, two experts square off on the difficult choice of trying to reduce the usage of one of two drugs with well-known side effects after kidney transplantation. [Abstract]

Johnson TS, Fisher M, Haylor JL, Hau Z, Skill NJ, Jones R, Saint R, Coutts I, Vickers ME, El Nahas AM, Griffin M
Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease.
J Am Soc Nephrol. 2007 Dec;18(12):3078-88. [Abstract]

Yang W, Israni RK, Brunelli SM, Joffe MM, Fishbane S, Feldman HI
Hemoglobin variability and mortality in ESRD.
J Am Soc Nephrol. 2007 Dec;18(12):3164-70.
Hemoglobin levels vary substantially over time in hemodialysis patients, and this variability may portend poor outcomes. For a given patient, hemoglobin concentration over time can be described by absolute levels, rate of change, or by the difference between observed level and expected level based on the preceding trend (i.e., seemingly random variability). We investigated the independent associations of these different methods of describing hemoglobin over time with mortality in a retrospective cohort of 34,963 hemodialysis patients. Hemoglobin concentration over time was modeled with linear regression for each subject, and the model was then used to define the subject's absolute level of hemoglobin (intercept), temporal trend in hemoglobin (slope), and hemoglobin variability (residual standard deviation). Survival analyses indicated that each 1g/dl increase in the residual standard deviation was associated with a 33% increase in rate of death, even after adjusting for multiple covariates. Patient characteristics accounted for very little of the variation in our hemoglobin variability metric (R2 = 0.019). We conclude that greater hemoglobin variability is independently associated with higher mortality. [Abstract]

Komenda P, Beaulieu M, Seccombe D, Levin A
Regional Implementation of Creatinine Measurement Standardization.
J Am Soc Nephrol. 2007 Nov 14;
Because patients may receive care at multiple locations within a geographic area, serum creatinine measurements must be standardized across laboratories to enable comparisons of reported estimated glomerular filtration rate (eGFR). The results of a successful creatinine standardization program designed to minimize the contribution of laboratory error to the reporting of eGFR are reported; 107 laboratories, which tested creatinine on 124 analyzers from six different manufacturers, voluntarily participated. Each laboratory received a correction factor to apply to its creatinine measurements to standardize them to the isotope dilution mass spectrometry reference method. The adjusted values were then used to calculate eGFR using the Modification of Diet in Renal Disease (MDRD) equation. The standardization program reduced the average total error in the measurement of creatinine from 23.9 to 8.7% and the average analytical bias from 16.5 to 2.7%. Implementing this program on a larger scale could reduce the rate of incorrect classification of stage 3 chronic kidney disease by 84%. [Abstract]

Prad�re JP, Klein J, Gr�s S, Guign� C, Neau E, Valet P, Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra JP
LPA1 receptor activation promotes renal interstitial fibrosis.
J Am Soc Nephrol. 2007 Dec;18(12):3110-8.
Tubulointerstitial fibrosis in chronic renal disease is strongly associated with progressive loss of renal function. We studied the potential involvement of lysophosphatidic acid (LPA), a growth factor-like phospholipid, and its receptors LPA(1-4) in the development of tubulointerstitial fibrosis (TIF). Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) for up to 8 d, and kidney explants were prepared from the distal poles to measure LPA release into conditioned media. After obstruction, the extracellular release of LPA increased approximately 3-fold. Real-time reverse transcription PCR (RT-PCR) analysis demonstrated significant upregulation in the expression of the LPA(1) receptor subtype, downregulation of LPA3, and no change of LPA2 or LPA4. TIF was significantly attenuated in LPA1 (-/-) mice compared to wild-type littermates, as measured by expression of collagen III, alpha-smooth muscle actin (alpha-SMA), and F4/80. Furthermore, treatment of wild-type mice with the LPA1 antagonist Ki16425 similarly reduced fibrosis and significantly attenuated renal expression of the profibrotic cytokines connective tissue growth factor (CTGF) and transforming growth factor beta (TGFbeta). In vitro, LPA induced a rapid, dose-dependent increase in CTGF expression that was inhibited by Ki16425. In conclusion, LPA, likely acting through LPA1, is involved in obstruction-induced TIF. Therefore, the LPA1 receptor might be a pharmaceutical target to treat renal fibrosis. [Abstract]

Wijnhoven TJ, Lensen JF, Wismans RG, Lefeber DJ, Rops AL, van der Vlag J, Berden JH, van den Heuvel LP, van Kuppevelt TH
Removal of heparan sulfate from the glomerular basement membrane blocks protein passage.
J Am Soc Nephrol. 2007 Dec;18(12):3119-27.
Heparan sulfate (HS) within the glomerular basement membrane (GBM) is thought to play a major role in the charge-selective properties of the glomerular capillary wall. Recent data, however, raise questions regarding the direct role of HS in glomerular filtration. For example, in situ studies suggest that HS may prevent plasma macromolecules from clogging the GBM, keeping it in an "open" state. We evaluated this potential role of HS in vivo by studying the passage of protein through the glomerular capillary wall in the presence and absence of HS. Intravenous administration of neuraminidase removed neuraminic acid--but not HS--from the GBM, and this led to albuminuria. Concomitant removal of HS with heparinase III, confirmed by ultrastructural imaging, prevented the development of albuminuria in response to neuraminidase treatment. Taken together, these results suggest that HS keeps the GBM in an open state, facilitating passage of proteins through the glomerular capillary wall. [Abstract]

Li L, Truong P, Igarashi P, Lin F
Renal and bone marrow cells fuse after renal ischemic injury.
J Am Soc Nephrol. 2007 Dec;18(12):3067-77. [Abstract]

Shah P, Tramontano A, Makker SP
Intramolecular epitope spreading in Heymann nephritis.
J Am Soc Nephrol. 2007 Dec;18(12):3060-6.
Immunization with megalin induces active Heymann nephritis, which reproduces features of human idiopathic membranous glomerulonephritis. Megalin is a complex immunological target with four discrete ligand-binding domains (LBDs) that may contain epitopes to which pathogenic autoantibodies are directed. Recently, a 236-residue N-terminal fragment, termed "L6," that spans the first LBD was shown to induce autoantibodies and severe disease. We used this model to examine epitope-specific contributions to pathogenesis. Sera obtained from rats 4 weeks after immunization with L6 demonstrated reactivity only with the L6 fragment on Western blot, whereas sera obtained after 8 weeks demonstrated reactivity with all four recombinant fragments of interest (L6 and LBDs II, III, and IV). We demonstrated that the L6 immunogen does not contain the epitopes responsible for the reactivity to the LBD fragments. Therefore, the appearance of antibodies directed at LBD fragments several weeks after the primary immune response suggests intramolecular epitope spreading. In vivo, we observed a temporal association between increased proteinuria and the appearance of antibodies to LBD fragments. These data implicate B cell epitope spreading in antibody-mediated pathogenesis of active Heymann nephritis, a model that should prove valuable for further study of autoimmune dysregulation. [Abstract]

Recent Articles in American Journal of Physiology. Renal physiology

Lee HT, Kim M, Song JH, Chen SW, Gubitosa G, Emala Sr CW
Sevoflurane mediated TGF-{beta}1 signaling in renal proximal tubule cells.
Am J Physiol Renal Physiol. 2007 Dec 5; .
Several volatile anesthetics including sevoflurane protect against renal ischemia reperfusion (IR) injury in vivo by reducing necrosis and inflammation. Furthermore, in cultured renal tubule cells, sevoflurane directly induced the phosphorylation of the cytoprotective kinases, extracellular signal-regulated protein kinase (ERK) and Akt, upregulated heat shock protein 70 (HSP70) and attenuated nuclear translocation of the pro-inflammatory transcription factor NFkappaB. Subsequently, we showed that sevoflurane increased the release of TGF-beta1 in human proximal tubule (HK-2) cells via externalization of plasma membrane phosphatidylserine (PS) and this increase in TGF-beta1 protected HK-2 cells against hydrogen peroxide-mediated necrosis. In this study, we wanted to determine whether the sevoflurane-mediated phosphorylation of ERK and Akt, induction of HSP70 and reduction in NFkappaB activation are due to TGF-beta1 receptor mediated signaling after PS externalization in HK-2 cells. Exogenous TGF-beta1 as well as a liposome mixture containing PS mimicked sevoflurane-mediated ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Sevoflurane as well as TGF-beta1 caused the nuclear translocation of the SMAD3 transcription factor in HK-2 cells. Furthermore, a neutralizing TGF-beta1 antibody or exogenous annexin to bind PS prevented sevoflurane induced ERK and Akt phosphorylation and HSP70 induction in HK-2 cells. Finally, a TGF-beta1 antibody as well as annexin attenuated the reduction in nuclear translocation of NFkappaB by sevoflurane. Therefore we demonstrate in this study that sevoflurane-mediated cytoprotective and anti-inflammatory effects in HK-2 cells are at least partially due to the externalization of PS and activation of TGF-beta1 signaling pathways. Key words: acute renal failure, Akt, volatile anesthetic, ERK. [Abstract]

Bing Y, Xu J, Harris RC, Zhang MZ
Renal Localization and Regulation of 15-Hydroxyprostaglandin Dehydrogenase.
Am J Physiol Renal Physiol. 2007 Dec 5;
Tissue prostaglandin levels are determined by both biosynthesis and catabolism. The current studies report the expression and localization of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in prostaglandin catabolism in the kidneys. We also investigated potential interactions between 15-PGDH and cyclooxygenase (COX), a key enzyme in prostaglandin biosynthesis. Both 15-PGDH mRNA and protein levels were significantly higher in kidney cortex than papilla, which is opposite to the expression pattern of COX-2. In situ hybridization indicated that 15-PGDH mRNA was mainly localized to the tubular epithelial cells in kidney cortex and outer medulla, but not in the glomerulus or papilla. Dual immunofluorescent staining indicated that 15-PGDH was expressed in the proximal tubule, medullary and cortical thick ascending limbs and cortical and outer medullary collecting duct but not in the macula densa or papilla. 15-PGDH levels were significantly lower in a macula densa cell line (MMDD1) than a proximal tubule cell line. Although a high salt-diet decreased COX-2 expression in macula densa, it increased macula densa 15-PGDH expression in both mouse and rat kidneys. In MMDD1 cells, a COX-2 inhibitor increased 15-PGDH while a COX-1 inhibitor had no effect. Furthermore, intense 15-PGDH immunofluorescent staining was found in both macula densa and glomerulus in COX-2 knockout mice. The intrarenal distribution of 15-PGDH and its interactions with COX-2 suggest that differential regulation of COX-2 and 15-PGDH may play an important role in determining levels of prostaglandins involved in regulation of salt, volume, and blood pressure homeostasis. Key words: prostaglandin, cyclooxygenase, macula densa. [Abstract]

Lynch IJ, Rudin A, Xia SL, Stow LR, Shull GE, Weiner ID, Cain BD, Wingo CS
Impaired Acid Secretion in Cortical Collecting Duct Intercalated Cells from H,K-ATPase-deficient Mice: Role of HK Isoforms.
Am J Physiol Renal Physiol. 2007 Dec 5;
Two classes of H pumps, H,K-ATPase and H-ATPase, contribute to luminal acidification and HCO3 secretion in the collecting duct (CD). At least two H,K-ATPase α-subunits are expressed in the CD: HKα1 and HKα2. Both exhibit K-dependence but have different inhibitor sensitivities. The HKα1 H,K-ATPase is Sch-28080-sensitive whereas the pharmacological profile of the HKα2 H,K-ATPase is not completely understood. The present study used a non-pharmacological, genetic approach to determine the contribution of HKα1 and HKα2 to cortical CD (CCD) intercalated cell (IC) proton transport in mice fed a normal diet. Intracellular pH (pHi) recovery was determined in ICs using in vitro microperfusion of CCD after an acute intracellular acid load in wild-type (WT) mice and mice of the same strain lacking expression of HKα1, HKα22, or both H,K-ATPases (HKα1,2). A-type and B-type ICs were differentiated by luminal loading with BCECF-AM and peritubular chloride removal from CO2/HCO3 buffered solutions to identify the membrane locations of Cl/HCO3 exchange activity. H-ATPase- and Na/H exchange-mediated H transport were inhibited with bafilomycin A1 (100 nM) and ethyl-isopropyl-amiloride (EIPA 10 μM), respectively. Here we report: (1) initial pHi and buffering capacity were not significantly altered in the ICs of HKα deficient mice; (2) either HKα1 or HKα2 deficiency resulted in slower acid extrusion in ICs; and (3) A-type ICs from HKα1,2 deficient mice had significantly slower acid extrusion when compared to the A-type ICs from HKα1 deficient mice alone. Key words: potassium, microperfusion, pH, acid-base balance, P-type ATPase. [Abstract]

Giehl K, Graness A, Goppelt-Struebe M
The small GTPase Rac1 is a regulator of mesangial cell morphology and thrombospondin-1 expression.
Am J Physiol Renal Physiol. 2007 Nov 28;
Thrombospondin-1 (TSP-1), which is synthesized by mesangial cells, is known for its anti-angiogenic activity and its ability to activate latent TGFbeta. TSP-1 is upregulated in renal diseases associated with tissue remodeling. Therefore, we hypothesized that the expression of TSP-1 might be modulated by changes in cell morphology involving proteins of the Rho family. Spreading of mesangial cells after detachment and reseeding was characterized by the formation of lamellipodia and focal adhesions, pointing towards a Rac-1-mediated rearrangement of actin structures. Clustering of focal adhesion proteins was also observed in a model system of nocodazole-induced disruption of microtubules. These morphological alterations were impeded by pharmacological inhibition of Src-family kinases, of the small GTPase Rac-1, or by downregulation of Rac-1 by siRNA. Upon cell spreading, TSP-1 was upregulated in the absence and much more prominently in the presence of serum, but also after nocodazole treatment. TSP-1 upregulation was controlled by activation of Src-family kinases, ERK 1/2 and Rac-1, whereas activation of RhoA-ROCK signaling was not linked to TSP-1 induction. We thus provide evidence that TSP-1 expression is induced by common signaling pathways, which are activated by morphological alterations of renal mesangial cells or by soluble factors as contained in serum, and these pathways include Src-family kinases, ERK 1/2 and Rac-1. Our data suggest that tissue remodeling activates gene expression of pathophysiologically relevant proteins such as TSP-1. Key words: Cytoskeleton, Rho proteins, Src kinases. [Abstract]

Li XC, Zhuo JL
In vivo regulation of AT1a receptor-mediated uptake of [125I]-Val5-angiotensin II in the kidney and adrenals of AT1a receptor-deficient mice.
Am J Physiol Renal Physiol. 2007 Nov 28;
Using AT1a receptor-deficient mice (Agtr1a-/-) and in vivo autoradiography, we tested the hypothesis that intracellular uptake of angiotensin II (Ang II) in the kidney and adrenals is primarily mediated by AT1a receptors and the response is regulated by prevailing endogenous Ang II. Wild-type (Agtr1a+/+) and Agtr1a-/- mice were pretreated with captopril (25 mg/kg/day) or losartan (10 mg/kg/day) for 2 weeks before [(125)I]-Val(5)-Ang II was infused for 60 min. Intracellular uptake of [(125)I]-Val(5)-Ang II was determined by quantitative in vivo autoradiography after circulating [(125)I]-Val(5)-Ang II was washed out. Compared with wild-types, basal intracellular Ang II levels were 65% lower in the kidney (p<0.001), but plasma Ang II levels were 3-folds higher in Agtr1a-/- mice (p<0.01). While plasma [(125)I]-Val(5)-Ang II levels were similar, urinary excretion of [(125)I]-Val(5)-Ang II was 4-folds higher in Agtr1a-/- mice (p<0.001). By contrast, intracellular [(125)I]-Val(5)-Ang II levels were 80% lower in the kidney and adrenals of Agtr1a-/- mice (p<0.01). Captopril decreased endogenous plasma and renal Ang II levels (p<0.01), but it increased intracellular uptake of [(125)I]-Val(5)-Ang II in the kidney and adrenals of both wild-type and Agtr1a-/- mice (p<0.01). Losartan largely blocked renal and adrenal uptake of [(125)I]-Val(5)-Ang II in both wild-type and Agtr1a-/- mice. Thus 80% of intracellular Ang II uptake in the kidney and adrenals is mediated by AT1a receptors, whereas AT1b receptor- and other non receptor-mediated mechanisms account for 20% of the response. Our results suggest that AT1a receptor-mediated uptake of extracellular Ang II may play a physiological role in the kidney and adrenals. Key words: Adrenal glands, Angiotensin II, Autoradiography, kidney, Receptor-mediated endocytosis. [Abstract]

Feng NH, Lee HH, Shiang JC, Ma MC
Transient Receptor Potential Vanilloid Type 1 Channels Act as Mechanoreceptors and Cause Substance P Release and Sensory Activation in Rat Kidneys.
Am J Physiol Renal Physiol. 2007 Nov 21;
Stimulation of capsaicin receptors results in an increase in afferent renal nerve activity (ARNA), but it is unclear how capsaicin contributes to sensory activation intrarenally. Here, we studied the relationships between capsaicin receptor activation, substance P (SP) release, and the sensory response in the rat renal pelvis. Immunoblots showed that one of the capsaicin receptors, transient receptor potential vanilloid type 1 channel (TRPV1), was found in various renal tissues and was especially abundant in the renal pelvis, where most sensory nerve fibers originate. Interestingly, immunolabeling showed co-localization of TRPV1, SP, and the panneuronal marker PGP9.5 in the renal pelvis. Electrophysiological recordings showed that SP and capsaicin activated the same mechanosensitive ARNA in a single-unit preparation. Intrapelvic administration of capsaicin or a specific TRPV1 agonist, resiniferatoxin, resulted in a dose-dependent increase in multi-unit ARNA and SP release, and these effects were blocked by the TRVP1 blocker capsazepine. Inhibition of the SP receptor by L-703,606 largely prevented capsaicin- or resiniferatoxin-induced ARNA. Capsazepine also prevented intrapelvic pressure (IPP)-dependent ARNA activation and contralateral diuresis/natriuresis in the renorenal reflex at an IPP of 20 mmHg, but had no effect at an IPP of 50 mmHg. These data indicate that TRPV1, a low-pressure baroreceptor, is present in the renal pelvis and exclusively regulates neuropeptide release from primary renal afferent C-fibers in response to mechanostimulation. Key words: Transient receptor potential vanilloid type 1 channels, Mechanoreceptor, Substance P, Neurokinin-1 receptor, Renorenal reflex. [Abstract]

Rahuel C, Filipe A, Ritie L, El Nemer W, Patey-Mariaud N, Eladari D, Cartron JP, Simon-Assmann P, Le Van Kim C, Colin Y
Genetic inactivation of the laminin {alpha}5 chain receptor Lu/BCAM leads to kidney and intestinal abnormalities in the mouse.
Am J Physiol Renal Physiol. 2007 Nov 21;
Lu/BCAM has been recognized as unique receptor for laminin alpha5 chain in human red blood cells and as co-receptor in epithelial, endothelial and smooth muscle cells. Since limited information is available regarding the function of this adhesion glycoprotein in vivo, we generated Lu/BCAM-null mice and looked for abnormalities in erythroid cells as well as in kidney and intestine, two tissues showing alteration in laminin alpha5 chain deficient mice. We first showed that in contrast to human, wild type murine red cells failed to express Lu/BCAM. Lu/BCAM-null mice were healthy and developed normally. However, while no alteration of the renal function was evidenced, up to 90 % of the glomeruli from mutant kidneys exhibited abnormalities characterized by a reduced number of visible capillary lumens and irregular thickening of the glomerular basement membrane. Similarly, intestine analysis of mutant mice revealed smooth muscle coat thickening and disorganization. Since glomerular basement membrane and smooth muscle coat express laminin alpha5 chain and are in contact with cell types expressing Lu/BCAM in wild type mice, these results provide evidence that Lu/BCAM, as a laminin 521 receptor, is involved in vivo in the maintenance of normal basement membrane organization in the kidney and intestine. Key words: basement membrane , glomeruli, KO mice, intestine, Lu/BCAM. [Abstract]

Bae EH, Lee KS, Lee J, Ma SK, Kim NH, Choi KC, Frokiaer J, Nielsen S, Kim SY, Kim SZ, Kim SH, Kim SW
Effects of {alpha}-Lipoic Acid on Ischemia/Reperfusion-Induced Renal Dysfunction in Rats.
Am J Physiol Renal Physiol. 2007 Nov 21;
We investigated whether alpha-lipoic Acid (alpha-LA), an antioxidant, attenuates the ischemia/reperfusion (I/R)-induced dysregulation of these transporters. Male Sprague-Dawley rats were clamped of both renal pedicles for 40 minutes. alpha-LA (80 mg/kg) was administered intraperitoneally before and immediately after inducing the ischemia. After 2 days, the expression of aquaporins (AQPs), sodium transporters and nitric oxide synthases (NOS) was determined in the kidney by immunoblotting and immunohistochemistry. The expression of endothelin-1 (ET-1) mRNA was determined by real-time polymerase chain reaction. Activities of adenylyl cyclase and guanylyl cyclase were measured by stimulated generation of cAMP and cGMP, respectively. The expression of AQP1-3 as well as that of alpha-1 subunit of Na,K-ATPase, NHE3, NKCC2 and NCC was markedly decreased in response to I/R. The expression of type VI adenylyl cyclase was decreased in I/R-injury rats, which was counteracted by the treatment of alpha-LA. AVP-stimulated cAMP generation was blunted in I/R rats, which was then ameliorated by alpha-LA treatment. alpha-LA treatment attenuated the downregulation of AQPs and sodium transporters. The expression of endothelial NOS was decreased in I/R rats, which was prevented by alpha-LA. The cGMP generation in response to sodium nitroprusside was blunted in I/R rats, which was also significantly prevented by alpha-LA. The mRNA expression of ET-1 was increased, which was recovered to the control level by alpha-LA treatment. In conclusion, alpha-LA treatment prevents I/R-induced dysregulation of AQPs and sodium transporters in the kidney, possibly through preserving normal activities of local AVP/cAMP, NO/cGMP and ET systems. Key words: -lipoic acid, aquaporins, sodium transporters, I/R injury, endothelin. [Abstract]

Carattino MD, Passero CJ, Steren CA, Maarouf AB, Pilewski JM, Myerburg MM, Hughey RP, Kleyman TR
Defining an inhibitory domain in the alpha subunit of the epithelial sodium channel.
Am J Physiol Renal Physiol. 2007 Nov 21;
Epithelial sodium channels (ENaC) are processed by proteases as they transit the biosynthetic pathway. We recently observed that furin-dependent processing of the alpha subunit of ENaC at two sites within its extracellular domain is required for channel activation due to release of a 26-residue inhibitory domain. While channels with alpha subunits lacking the furin sites are not cleaved and have very low activity, channels lacking the furin sites as well as the tract between these sites (alphaD206-R231) are active. We analyzed channels with a series of deletions in the tract alphaD206-R231 and lacking the alpha subunit furin consensus sites in Xenopus laevis oocytes. We found an eight-residue tract that, when deleted, restored channel activity to the level found in oocytes expressing wild type ENaC. A synthetic peptide, LPHPLQRL, representing the tract alphaL211-L218 inhibited wild type ENaC expressed in oocytes with an IC50 of 0.9 microM, and inhibited channels expressed in collecting duct cells and human primary airway epithelial cells with IC50s of between ~50 to 100 microM. Analyses of peptides with deletions within this inhibitory tract indicate that eight residues is the minimal backbone length that is required for ENaC inhibition. Analyses of 8-mer peptides with conserved and non-conserved substitutions suggest that L(1), P(2), H(3), P(4), and L(8) are required for inhibitory activity. Our findings suggest that this eight-residue tract is a key conserved inhibitory domain that provides epithelial cells with a reserve of channels that can be activated as required by proteases. Key words: epithelial sodium channel, peptide inhibitors, proteases, furin. [Abstract]

Carlstrom M, Brown RD, Edlund J, Sallstrom J, Larsson E, Teerlink T, Palm F, Wahlin N, Persson AE
Role of Nitric Oxide Deficiency in the Development of Hypertension in Hydronephrotic Animals.
Am J Physiol Renal Physiol. 2007 Nov 21;
Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF-sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either L-NAME or L-arginine. Blood samples for ADMA, SDMA, L-arginine analysis were taken and the renal tissue was used for histology and determination of NOS proteins. TGF-characteristics were determined by stop-flow pressure technique before and after administration of 7-NI or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF-response were greater in the hydronephrotic group. 7-NI administration increased TGF-reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, nNOS inhibition had no effect. L-arginine attenuated TGF-response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and eNOS proteins were lower in animals with hydronephrosis. In conclusion, reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF-mechanism, plays an important role in the development of hypertension. Key words: hydronephrosis, hypertension, nitric oxide, tubuloglomerular feedback, ADMA. [Abstract]

Celie JW, Reijmers RM, Slot EM, Beelen RH, Spaargaren M, Ter Wee PM, Florquin S, van den Born J
Tubulointerstitial heparan sulfate proteoglycan changes in human renal diseases correlate with leukocyte influx and proteinuria.
Am J Physiol Renal Physiol. 2007 Nov 21;
Heparan sulfate proteoglycans (HSPGs) are well-known for their proposed role in glomerular filtration. In addition, HSPGs can bind the leukocyte adhesion molecule L-selectin and chemokines, suggesting a role in inflammation. We examined a panel of biopsies representing different human primary kidney diseases for L-selectin and monocyte chemoattractant protein-1 (MCP-1) binding. In various renal diseases L-selectin and MCP-1 binding to interstitial perivascular matrix HSPGs is increased, which is significantly associated with leukocyte influx. In proteinuric diseases including membranous glomerulopathy, minimal change disease, but also IgA nephropathy and lupus nephritis, increased binding of L-selectin and MCP-1 to tubular epithelial cell (TEC) HSPGs is observed, which colocalizes with increased basolateral syndecan-1 and anti-HS 10E4 staining. shRNA-mediated silencing demonstrates that syndecan-1 on TECs indeed mediates L-selectin binding. Increased TEC expression of IL-8 in biopsies of proteinuric patients suggests that the increase in luminal protein may activate TECs to increase expression of L-selectin and MCP-1 binding syndecan-1. Strikingly, urinary syndecan-1 from proteinuric patients is less capable of binding L-selectin compared to urinary syndecan-1 from healthy controls, although syndecan-1 concentrations are similar in both groups. Together, our data show pronounced tubulointerstitial HSPG alterations in primary kidney disease, which may affect the inflammatory response. Key words: adhesion molecule, chemokine, tubular epithelial cells, inflammation. [Abstract]

Kennedy DJ, Elkareh J, Shidyak A, Shapiro AP, Smaili S, Mutgi K, Gupta S, Tian J, Morgan E, Khouri S, Cooper CJ, Periyasamy SM, Xie Z, Malhotra D, Fedorova OV, Bagrov AY, Shapiro JI
Partial Nephrectomy as a Model for Uremic Cardiomyopathy in the Mouse.
Am J Physiol Renal Physiol. 2007 Nov 21;
Because of the plethora of genetic manipulations available in the mouse, we performed partial nephrectomy in the mouse and examined whether the phenotypical features of uremic cardiomyopathy described in humans and rats were also present in the murine model. 5/6(th) nephrectomy was performed using a combination of electrocautory to decrease renal mass on the left kidney and right surgical nephrectomy. This procedure produced substantial and persistent hypertension as well as increases in circulating concentrations of marinobufagenin. Invasive physiological measurements of cardiac function demonstrated that 5/6(th) nephrectomy resulted in impairment of both active and passive left ventricular relaxation at 4 weeks whereas tissue Doppler imaging detected changes in diastolic function after 6 weeks. Morphologically, hearts demonstrated enlargement and progressive fibrosis, and biochemical measurements demonstrated downregulation of the sarcoplasmic reticulum calcium ATPase as well as increases in collagen-1, fibronectin and vimentin expression. Our results suggest that partial nephrectomy in the mouse establishes a model of uremic cardiomyopathy which shares phenotypical features with the rat model as well as patients with chronic renal failure. Key words: Cardiomyopathy, renal failure, Reactive oxygen species, Cardiotonic steroids, Fibrosis. [Abstract]

Ohnishi H, Mizuno S, Nakamura T
Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acute renal failure.
Am J Physiol Renal Physiol. 2007 Nov 21;
During a progression of acute renal failure (ARF), renal tubular S3-segment is sensitive to ischemic stresses. For reversing tubular damage, resident tubular cells proliferate, and bone marrow-derived cells (BMDC) can be engrafted into injured tubules. However, how resident epithelium or BMDC are involved in tubular repair remains unknown. Using a mouse model of ARF, we examined whether hepatocyte growth factor (HGF) regulates a balance of resident cell proliferation and BMDC recruitment. Within 48-hours post-renal ischemia, tubular destruction became evident, followed by 2-waved regenerative events: 1) tubular cell proliferation between 2 and 4 days, along with an increase in blood HGF; and 2) appearance of BMDC in the tubules from 6 days post-ischemia. When anti-HGF IgG was injected in the earlier stage, tubular cell proliferation was inhibited, leading to an increase of BMDC in renal tubules. Under the HGF-neutralized states, stromal cell-derived factor-1 (SDF1) levels increased in renal tubules, associated with the enhanced hypoxia. Administrations of anti-SDF1-receptor IgG into ARF mice reduced the number of BMDC in interstitium and tubules. Thus, possible cascades include: 1) inhibition of tubular cell proliferation by neutralizing HGF leads to renal hypoxia and SDF1 up-regulation; and 2) BMDC are eventually engrafted in tubules through SDF1-mediated chemotaxis. Inversely, administration of recombinant HGF suppressed the renal hypoxia, SDF1 up-regulation and BMDC engraftment in ARF mice by enhancing resident tubular cell proliferation. Thus, we conclude that HGF is a positive regulator for eliciting resident tubular cell proliferation, and SDF1 for BMDC engraftment during the repair process of ARF. Key words: acute renal failure, tubular repair, HGF, SDF1, hypoxia. [Abstract]

Abdullah HI, Pedraza PL, McGiff JC, Ferreri NR
CaR activation increases TNF production by mTAL cells via a Gi-dependent mechanism.
Am J Physiol Renal Physiol. 2007 Nov 21;
We evaluated the contribution of CaR-mediated Gi-coupled signaling to TNF production in mTAL cells. A selective Gi inhibitor, Pertussis toxin (PTX), but not the inactive B-oligomer binding subunit, abolished CaR-mediated increases in TNF production. The inhibitory effect of PTX was partially reversed by using an adenylate cyclase inhibitor. CaR-mediated TNF production also was partially reversed by a cAMP analog, 8-Br-cAMP. IP1 accumulation was CaR-dependent and blocked by PI-PLC; partial inhibition also was observed with PTX. CaR increased calcineurin (CaN) activity by approximately 3-fold and PTX prevented CaR-mediated increases in CaN activity, an NFAT cis-reporter construct, and a TNF promoter construct. The interaction between Gi and PKC was determined, as we previously showed that CaR-mediated TNF production was CaN- and NFAT-mediated and Gq-dependent. CaR activation increased PKC activity by 2-fold, an effect abolished by transient transfection with a dominant negative CaR construct, R796W, or pretreatment with PTX. Inhibition with the pan specific PKC inhibitor, GF 109203X (20 nM) abolished CaR-mediated increases in activity of CaN, an NFAT reporter, and a TNF promoter construct. Collectively, the data suggest that Gi-coupled signaling contributes to NFAT-mediated TNF production, in a CaN- and PKC-dependent manner, and may be part of a CaR mechanism to regulate mTAL function. Moreover, concurrent Gq and Gi signaling is required for CaR-mediated TNF production in mTAL cells via a CaN/NFAT pathway that is PKC-dependent. Understanding CaR-mediated signaling pathways that regulate TNF production in the mTAL is crucial to defining novel mechanisms that regulate extracellular fluid volume and salt balance. Key words: TNF, Calcium-sensing receptor, G-proteins, loop of Henle, NFAT. [Abstract]

Oh DJ, Dursun B, He Z, Lu L, Hoke TS, Ljubanovic D, Faubel S, Edelstein CL
Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice.
Am J Physiol Renal Physiol. 2007 Nov 14;
Fractalkine (CX3CL1) is expressed on injured endothelial cells and is a potent chemoattractant and adhesion molecule for macrophages carrying the fractalkine receptor (CX3CR1). The aim of this study was to investigate the role of CX3CL1, and its ligand CX3CR1, in ischemic acute renal failure (ARF) in mice. On immunoblotting, CX3CL1 protein expression in the kidney increased markedly in ischemic ARF. On immunofluorescence staining, the intensity of CX3CL1 staining in blood vessels was significantly more prominent in ischemic ARF compared to controls. A specific anti-CX3CR1 antibody (25 microg IP 1hr before induction of ischemia) was functionally and histologically protective against ischemic ARF. CX3CR1 is predominantly expressed on macrophages. Macrophage infiltration in the kidney in ischemic ARF was significantly decreased after anti-CX3CR1 antibody treatment. To determine the role of macrophages in ischemic ARF, macrophages in the kidney were depleted using liposomal-encapsulated clodronate (LEC). LEC resulted in significant functional and histological protection against ischemic ARF. In summary, in ischemic ARF, 1) there is upregulation of CX3CL1 protein in the kidney, specifically in blood vessels, 2) CX3CR1 inhibition using a specific antibody is partially protective and is associated with reduced macrophage infiltration in the kidney, 3) macrophage depletion in the kidney is protective. Key words: fractalkine, macrophages, acute renal failure. [Abstract]

Shi H, Patschan D, Dietz GP, Bahr M, Plotkin M, Goligorsky MS
Glial cell line-derived neurotrophic growth factor increases motility and survival of cultured mesenchymal stem cells and ameliorates acute kidney injury.
Am J Physiol Renal Physiol. 2007 Nov 14;
Glial cell line-derived neurotrophic growth factor (GDNF), a member of the transforming growth factor family, is necessary for renal organogenesis and exhibits changes of expression in models of renal disease. Having demonstrated the participation of nestin-expressing cells in renoprotection, we hypothesized that growth factors and transcription factors similar to those operating in the nervous system should be also operant in the kidney. Using cultured kidney-derived mesenchymal stem cells (MSC) abundantly expressing nestin, we confirmed expression of GDNF by these cells and demonstrated GDNF-induced expression of GDNF. The cellular expression of nestin paralleled that of GDNF expression. Immunohistochemical and Western blot analyses of kidneys obtained from post-ischemic mice showed that expression of GDNF was much enhanced in the renal cortex, a pattern similar to the previously reported expression of nestin. GDNF-treated mice were protected against acute ischemia. To address potential mechanisms of the observed renoprotection, in vitro studies showed that GDNF accelerated MSC migration in a wound healing assay. Hypoxia did not accelerate the motility of MSC and reduced the expression of GDNF in MSC by approximately 2-fold. GDNF was cytoprotective against oxidative stress-induced apoptotic death of MSC. Collectively, these data establish a) an autoregulatory circuit of GDNF-induced GDNF expression in renal MSC; b) induction of GDNF expression in post-ischemic kidneys; c) the ability of exogenous GDNF to ameliorate ischemic renal injury; and d) a possible contribution of GDNF-induced motility and improved survival of MSC to renoprotection. Key words: Glial cell-derived neurotrophic growth factor, nestin, acute kidney injury, mesenchymal stem cell, apoptosis. [Abstract]

Pollock JS, Carmines PK
Diabetic Nephropathy: Nitric Oxide and Renal Medullary Hypoxia.
Am J Physiol Renal Physiol. 2007 Nov 14;
There is no abstract associated with an Editorial Focus Key words: diabetic nephropathy, renal medulla, hypoxia, nitric oxide. [Abstract]

Habib SL, Riley DJ, Mahimainathan L, Bhandari B, Choudhury GG, Abboud HE
Tuberin Regulates the DNA Repair Enzyme OGG1.
Am J Physiol Renal Physiol. 2007 Nov 7;
The tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2. The TSC-2 gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors, both angiomyolipomas and renal cell carcinomas. We investigated a potential role for tuberin in regulating a key DNA repair pathway. Downregulation of tuberin in human renal epithelial cells using siRNA resulted in a marked decrease in the abundance of the 8-oxoG-DNA glycosylase (OGG1). Mouse embryonic fibroblasts deficient in tuberin (Tsc2(-/-) and Tsc2(+/-)) also had markedly decreased OGG1 mRNA and protein expression, as well as undetectable OGG1 activity accompanied by accumulation of 8-oxodG. Gel shift analyses and chromatin immunoprecipatation identified the transcription factor NF-YA as a regulator of OGG1 activity. The binding of NF-YA to the OGG1 promoter was significantly reduced in Tsc2(-/-) compared to Tsc2(+/+) cells. Introduction of Tsc2 cDNA into the tuberin-deficient cells restored NF-YA and OGG1 expression. Transcriptional activity of the OGG1 promoter was also decreased in tuberin-null cells. In addition, mutation of both CAAT boxes, the sites to which NF-YA binds, completely inhibits OGG1 promoter activity. These data provide the first evidence that tuberin regulates a specific DNA repair enzyme, OGG1. This regulation may be important in the pathogenesis of kidney tumors in patients with TSC. Key words: Tuberin, DNA Repair, NF-YA. [Abstract]

Dominguez JH, Mehta JL, Li D, Wu P, Kelly KJ, Packer CS, Temm CJ, Goss E, Cheng L, Zhang S, Patterson CE, Hawes JW, Peterson RG
Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: Ablation of renal vascular and epithelial manifestations.
Am J Physiol Renal Physiol. 2007 Nov 7;
.LOX-1 is a multifunctional membrane receptor that binds and internalizes oxidized LDL (oxLDL). We tested the hypothesis that blockade of LOX-1 with an anti-LOX-1 antibody limits nephropathy in male rats with diabetes and dyslipidemia (ZS rats: F1 hybrid product of Zucker fatty diabetic rats and Spontaneous Hypertensive Heart Failure rats). Lean ZS rats (LM) were controls, while untreated obese ZS (OM), ZS obese rats injected with non-specific rabbit IgG (OM-IgG, 2 microg intravenous injection given weekly), and obese ZS rats given anti-LOX-1 rabbit antibody (OM-Ab, 2 microg intravenous injection given weekly) were the experimental groups. The rats were treated from 6 to 21 weeks of age. All obese groups had severe dyslipidemia, and hyperglycemia. Kidneys of obese rats expressed LOX-1 in capillaries and tubules, were larger, accumulated lipid, had intense oxidative stress, leukocyte infiltration, depressed mitochondrial enzyme level and function, and peritubular fibrosis (all p<0.05 vs lean ZS rats). Injections with LOX-1 antibody limited these abnormalities (p<0.01 vs. data in OM or OM-lgG rats). In vitro, renal epithelial LOX-1 expression was verified in a cultured proximal tubule cell line. Our study indicates that anti-LOX-1 (vascular and epithelial) therapy may effectively reverse critical pathogenic elements of nephropathy in diabetes and dyslipidemia. Key words: renal failure, diabetic nephropathies, atherosclerosis, oxidized LDL receptors. [Abstract]

Sanchez-Lopez E, Rodriguez-Vita J, Cartier C, Ruperez M, Esteban V, Carvajal G, Rodrigues-Diez R, Plaza JJ, Egido J, Ruiz-Ortega M
Inhibitory effect of interleukin-1-{beta} on Angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells.
Am J Physiol Renal Physiol. 2007 Nov 7;
Connective tissue growth factor (CTGF) is overexpressed in kidney diseases associated with extracellular matrix (ECM) accumulation. Angiotensin II (AngII) participates in renal fibrosis by the upregulation of growth factors, including CTGF, and ECM proteins, such as type IV collagen. During renal injury, AngII and the macrophage-produced cytokine interleukin-1-beta (IL-1-beta) may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between AngII and IL-1-beta in renal fibrosis. For this reason, in cultured mesangial cells (MC), we have investigated whether IL-1-beta could regulate AngII-mediated collagen accumulation and the mechanisms underlying this process. In MC, CTGF is a downstream mediator of type IV collagen production induced by AngII. IL-1-beta did not increase the production of CTGF and type IV collagen, but significantly inhibited AngII-induced CTGF and type IV collagen overexpression. Moreover, IL-1-beta also inhibited type IV collagen upregulation caused by exogenous recombinant CTGF. Matrix metalloproteinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of IL-1-beta and AngII caused a synergistic increase on MMP-9 ge