AJP Renal Physiology (Am J Physiol Ren Physiol)

Publisher: American Physiological Society (1887- ), American Physiological Society

Journal description

The American Journal of Physiology: Renal Physiology publishes original manuscripts on a broad range of subjects relating to the kidney, urinary tract, and their respective cells and vasculature, as well as to the control of body fluid volume and composition. Studies may involve human or animal models, individual cell types, and isolated membrane systems. Authors are encouraged to submit reports on research using a wide range of approaches to the study of function in these systems, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, and physiological methodologies. Papers on the pathophysiological basis of disease processes of the kidney, urinary tract, and regulation of body fluids are also encouraged.

Current impact factor: 4.42

Impact Factor Rankings

Additional details

5-year impact 0.00
Cited half-life 5.80
Immediacy index 0.99
Eigenfactor 0.05
Article influence 1.34
Website American Journal of Physiology - Renal Physiology website
Other titles American journal of physiology., Renal physiology, Renal physiology, AJP: renal physiology
ISSN 1522-1466
OCLC 40065092
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

American Physiological Society

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Conditions
    • NIH, Wellcome Trust, HHMI, MRC and BBSRC authors will on their behalf have the Publisher's version/PDF deposited in PubMed Central for release 12 months after publication
    • Publisher's version/PDF cannot be used
  • Classification
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously shown that vasa recta pericytes are known to dilate vasa recta capillaries in the presence of PGE2 and contract vasa recta capillaries when endogenous production of PGE2 is inhibited by the non-selective NSAID, indomethacin. In this study, we have used a live, rat kidney slice model to build on these initial observations and provide novel data that demonstrates non-selective, COX-1- and COX-2-selective NSAIDs act via medullary pericytes to elicit a reduction of vasa recta diameter. Real-time images of in situ vasa recta were recorded and vasa recta diameter at pericyte and non-pericyte sites measured off-line. PGE2 and epoprostenol (a prostacyclin analogue) evoked dilation of vasa recta specifically at pericyte sites and PGE2 significantly attenuated pericyte-mediated constriction of vasa recta evoked by both ET-1 and Ang-II. NSAIDs, indomethacin>SC560>celecoxib>meloxicam, evoked significantly greater constriction of vasa recta capillaries at pericyte sites than at non-pericyte sites and indomethacin significantly attenuated the pericyte-mediated vasodilation of vasa recta evoked by both PGE2, epoprostenol, bradykinin and SNAP. Moreover, a reduction in PGE2 was measured using an enzyme immune assay following superfusion of kidney slices with indomethacin. In addition immunohistochemical techiques were employed to demonstrate the population of EP receptors in the medulla. Collectively, these data demonstrate that pericytes are sensitive to changes in PGE2 concentration and may serve as the primary mechanism underlying NSAID-associated renal injury and/or further compound associated tubular damage. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00199.2015
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    ABSTRACT: Although renin is a critical regulatory enzyme of the cardiovascular system, its roles in organogenesis and the establishment of cardiovascular homeostasis remain unclear. Mammalian renin-expressing cells are widespread in embryonic kidneys but highly restricted, specialised endocrine cells in adults. With a functional pronephros, embryonic zebrafish are ideal for delineating the developmental functions of renin-expressing cells and mechanisms governing renin transcription. Larval zebrafish renin expression originates in the mural cells of the juxtaglomerular anterior mesenteric artery and subsequently at extra-renal sites. The role of renin was determined by assessing responses to renin-angiotensin system blockade, salinity variation, and renal perfusion ablation. Renin expression did not respond to renal flow ablation, but was modulated by inhibition of angiotensin converting enzyme and altered salinity. Our data in larval fish is consistent with conservation of renin's physiologic functions. Using transgenic renin reporter fish, with mindbomb and cloche mutants, we show that Notch signalling and endothelium are essential for developmental renin expression. Following inhibition of angiogenesis, renin-expressing cells precede angiogenic sprouts. Arising from separate lineages, but relying on mutual interplay with endothelial cells, renin-expressing cells are amongst the earliest mural cells observed in larval fish, performing both endocrine and paracrine functions. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00247.2015
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    ABSTRACT: Purines induce transient contraction and prolonged relaxation of detrusor muscles. Transient contraction is likely due to activation of inward currents in smooth muscle cells, and prolonged relaxation may be due to activation of small conductance Ca(2+)-activated K(+) (SK) channels via P2Y1 receptors expressed by detrusor PDGFRα(+) cells. We investigated whether other subtypes of P2Y receptors are involved in the activation of SK channels in PDGFRα(+) cells of detrusor muscles. Quantitative analysis of transcripts revealed that P2ry2, P2ry4 and P2ry14 are expressed in PDGFRα(+) cells of P2ry1-/- /eGFP mice at similar levels as in wild type mice. UTP, a P2Y2/P2Y4 agonist, activated large outward currents in detrusor PDGFRα(+) cells. SK channel blockers and an inhibitor of phospholipase C completely abolished currents activated by UTP. In contrast, UTP activated non-selective cation currents in smooth muscle cells. Under current-clamp (I=0), UTP induced significant hyperpolarization of PDGFRα(+) cells. MRS2500, a P2Y1 antagonist, did not affect the UTP-activated outward currents in PDGFRα(+) cells from wild type, and activation of outward currents by UTP was retained in P2ry1-/-/eGFP mice. As a negative control, we tested the effect of MRS2693, a selective P2Y6 agonist. This compound did not activate outward currents in PDGFRα(+) cells, and currents activated by UTP were unaffected by MRS2578, a selective P2Y6 antagonist. Nonselective P2Y receptor blocker inhibited UTP-activated outward currents in PDGFRα(+) cells. Our data demonstrate that P2Y2 and/or P2Y4 receptors function, in addition to P2Y1 receptors in activating SK currents in PDGFRα(+) cells and possibly in mediating purinergic relaxation in detrusor muscles. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00156.2015
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    ABSTRACT: Plasma Membrane Ca(2+)-ATPase's (PMCA) participate in epithelial Ca(2+) transport and intracellular Ca(2+) signaling. The Pmca4 isoform is enriched in distal nephron isolates and decreased in mice lacking the epithelial Ca(2+) channel, Trpv5. We therefore hypothesized that Pmca4 plays a significant role in transcellular Ca(2+) flux and investigated the localization and regulation of Pmca4 in Ca(2+)-transporting epithelia. Using antibodies directed specifically against Pmca4, we found it expressed only in the smooth muscle layer of mouse and human intestine, while pan-specific Pmca antibodies detected Pmca1 in lateral membranes of enterocytes. In kidney, Pmca4 showed broad localization to the distal nephron. In mouse, expression was most abundant in segments coexpressing the epithelial Ca(2+) channel, Trpv5. Significant, albeit lower expression, was also evident in the region encompassing the cortical thick ascending limbs, macula densa, and early distal tubules as well as smooth muscle layers surrounding renal vessels. In human kidney, a similar pattern of distribution was observed, with highest PMCA4 expression in NCC positive tubules. Electron microscopy demonstrated Pmca4 localization in distal nephron cells at both the basolateral membrane and intracellular perinuclear compartments, but not submembranous vesicles, suggesting rapid trafficking to the plasma membrane is unlikely to occur in vivo. Pmca4 expression was not altered by perturbations in Ca(2+) balance, pointing to a housekeeping function of the pump in Ca(2+) transporting epithelia. In conclusion, Pmca4 shows a divergent expression pattern in Ca(2+) transporting epithelia, inferring diverse roles for this isoform not limited to transepithelial Ca(2+) transport. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00651.2014
  • AJP Renal Physiology 07/2015; 309(2):F179-80. DOI:10.1152/ajprenal.00094.2015
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    ABSTRACT: Although dietary phosphate restriction is important for treating hyperphosphatemia in patients with chronic kidney disease, it remains unclear whether a low protein diet (LPD), which includes low phosphate, has beneficial effects on malnutrition, inflammation, and vascular calcification. The effects of LPD on inflammation, malnutrition, and vascular calcification were therefore assessed in rats. Rats were fed a normal diet or diets containing 0.3% adenine and low/normal protein and low/high phosphate. After 6 weeks, serum and urinary biochemical parameters, systemic inflammation, and vascular calcification were examined. The protective effect of fetuin-A and albumin were assessed in cultured vascular smooth muscle cells. Rats fed the diet containing 0.3% adenine developed severe azotemia. LPD in rats fed high phosphate induced malnutrition (decreases in body weight, food intake, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-α and urinary oxidative stress marker). LPD decreased serum fetuin-A level and fetuin-A synthesis in the liver and increased serum calcium-phosphate precipitates. High phosphate diet increased aortic calcium content, which was enhanced by LPD. Reduced fetal calf serum in the medium of cultured vascular smooth muscle cells enhanced phosphate-induced formation of calcium-phosphate precipitates in the media and calcification of vascular smooth muscle cells, both of which were prevented by fetuin-A administration. Our results suggest that phosphate restriction by restricting dietary protein promotes vascular calcification by lowering systemic fetuin-A level and increasing serum calcium-phosphate precipitates and induces inflammation and malnutrition in uremic rats fed a high phosphate diet. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00017.2015
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    ABSTRACT: Editorial focus for F-00438-2014R3. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00301.2015
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    ABSTRACT: High mobility group box 1 is a damage-associated molecule implicated in mediating kidney dysfunction in sepsis and sterile inflammatory disorders. HMGB1 is a nuclear protein released extracellularly in response to infection or injury, where it interacts with TLR4 and other receptors to mediate inflammation. Previously we demonstrated that LPS inhibits HCO3 (-) absorption in the medullary thick ascending limb (MTAL) through a basolateral TLR4-ERK pathway. Here we examined whether HMGB1 could inhibit HCO3 (-) absorption through the same pathway. Adding HMGB1 to the bath decreased HCO3 (-) absorption by 24% in isolated, perfused rat and mouse MTALs. In contrast to LPS, inhibition by HMGB1 was preserved in MTALs from TLR4(-/-) mice and was unaffected by ERK inhibitors. Inhibition by HMGB1 was eliminated by the RAGE antagonist FPS-ZM1 and by neutralizing anti-RAGE antibody. Confocal immunofluorescence showed expression of RAGE in the basolateral membrane domain. Inhibition of HCO3 (-) absorption by HMGB1 through RAGE was additive to inhibition by LPS through TLR4 and to inhibition by Gram-positive bacterial molecules through TLR2. Bath amiloride, which selectively prevents inhibition of MTAL HCO3 (-) absorption mediated through NHE1, eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCO3 (-) absorption through a RAGE-dependent pathway distinct from TLR4-mediated inhibition by LPS. These studies provide new evidence that HMGB1-RAGE signaling acts directly to impair the transport function of renal tubules. They reveal a novel paradigm for sepsis-induced renal tubule dysfunction, whereby exogenous pathogen-associated molecules and endogenous damage-associated molecules act directly and independently to inhibit MTAL HCO3 (-) absorption through different receptor signaling pathways. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00227.2015
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    ABSTRACT: Proximal tubular injury and apoptosis are key mediators of development of kidney fibrosis, a hallmark of chronic kidney disease. However, the molecular mechanism by which tubular apoptotic cell death leads to kidney fibrosis is poorly understood. Here we tested the roles of Bax and Bak, two crucial proteins involved in intrinsic apoptotic cell death, in progression of kidney fibrosis. Mice with proximal tubule-specific Bax deletion, systemic deletion of Bak and dual deletion of Bax and Bak were subjected to unilateral ureteral obstruction (UUO). Dual deficiency of Bax and Bak inhibited tubular apoptosis and atrophy. Consistent with decreased tubular injury, dual ablation of Bax and Bak suppressed UUO-induced inflammation and kidney fibrosis with decreased tubular cell cycle arrest, expression of fibrogenic and inflammatory cytokines, and oxidative stress in the kidney. Bax or Bak deficiency was insufficient to prevent apoptosis and all other aforementioned malevolent effects, suggesting compensatory mediation by each other in the respective signaling pathways. These data suggest that dual ablation of Bax and Bak in the kidney is required to prevent UUO-induced tubular apoptosis and the consequent kidney inflammation and fibrosis. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00170.2015
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    ABSTRACT: We expanded a published mathematical model of an afferent arteriole smooth muscle cell in rat kidney (Edwards and Layton, Am J Physiol Renal Physiol 306: F34-F48, 2014) to understand how nitric oxide (NO) and superoxide (O2 (-)) modulate the arteriolar diameter and its myogenic response. The present model includes the kinetics of NO and O2 (-) formation, diffusion, and reaction. Also included are the effects of NO and its second messenger cGMP on Ca(2+) uptake and efflux into the cell, Ca(2+)-activated K+ currents, and myosin light chain phosphatase activity. In addition, the model accounts for pressure-induced increases in O2 (-) production, O2 (-)-mediated regulation of L-type Ca(2+) channel conductance, and increased O2 (-) production in spontaneous hypertensive rats (SHR). Our results indicate that elevated O$_2^-$ production in SHR is sufficient to account for observed differences between normotensive and hypertensive rats in the response of the afferent arteriole to NO synthase inhibition, Tempol, and angiotensin II at ba seline perfusion pressures. In vitro, whether the myogenic response is stronger in SHR remains uncertain. Our model predicts that if mechano-sensitive cation channels are not modulated by O$_2^-$, then fractional changes in diameter induced by pressure elevations should be smaller in SHR than in normotensive rats. Our results also suggest that most NO diffuses out of the smooth muscle cell without being consumed, whereas most O$_2^-$ is scavenged, by NO and superoxide dismutase. Moreover, the predicted effects of superoxide on arteriolar constriction are not predominantly due to its scavenging of NO. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00187.2015
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    ABSTRACT: The anti-aging gene klotho plays an important role in calcium and phosphate homeostasis. Membrane-bound klotho is an essential co-receptor for fibroblast growth factor 23 and can be cleaved by proteases, including a disintegrin and metalloproteinase (ADAM)10 and 17. Cleavage of klotho occurs at a site directly above the plasma membrane (α-cut) or between the KL1 and KL2 domain (β-cut), resulting in soluble full-length klotho or KL1 and KL2 fragments, respectively. The aim of the present study was to gain insight into the mechanisms behind klotho cleavage processes in the kidney. Klotho shedding was demonstrated using a Madin-Darby canine kidney cell line stably expressing klotho and human embryonic kidney 293 cells transiently transfected with klotho. We report klotho expression on both the basolateral and apical membrane, with a higher abundance of klotho at the apical membrane and in the apical media. ADAM17 and klotho mRNA expression was enriched in mouse distal convoluted and connecting tubules. In vitro ADAM/matrix metalloproteinase (MMP) inhibition by TNF484 resulted in a concentration-dependent inhibition of the α-cut, with a less specific effect on β-cut shedding. In vivo TNF484 treatment in wild type mice did not change urinary klotho levels. However, ADAM/MMP inhibition did increase renal and duodenal mRNA expression of phosphate transporters, while serum phosphate levels were significantly decreased. In conclusion, our data show that renal cells preferentially secrete klotho to the apical side, and suggest that ADAMs are responsible for α-cut cleavage. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00240.2014
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    ABSTRACT: Since polycystic kidney disease (PKD) was first noted over 30 years ago to have neoplastic parallels, there has been a resurgent interest in elucidating neoplasia-relevant pathways in PKD. Taking a non-targeted metabolomics approach in the B6(Cg)-Cys1cpk/J (cpk) mouse model of recessive PKD, we have now characterized metabolic reprogramming in these tissues leading to a glutamine-dependent TCA cycle shunt towards total 2-hydroxyglutarate (2-HG) production in cpk as compared to B6 wild type kidney tissue. After confirmation of increased 2-HG expression in immortalized collecting duct cpk cells as well as in human ARPKD tissue using targeted analysis, we show that the increase in 2-HG is likely due to glutamine-sourced α-ketoglutarate. In addition, cpk cells require exogenous glutamine for growth such that inhibition of glutaminase-1 decreases cell viability as well as proliferation. This study is a demonstration of the striking parallels between recessive PKD and cancer metabolism. Our data, once confirmed in other PKD models, suggest that future therapeutic approaches targeting this pathway, such as using glutaminase inhibitors, have the potential to open novel treatment options for renal cystic disease. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00238.2015
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    ABSTRACT: Leukemia inhibitory factory (LIF), as a member of interleukin-6 family, was reported ameliorating myocardial fibrosis and myocardial cell death. The purpose of this study was to investigate the effect of LIF on renal fibrosis and its underlying mechanism. Our results showed: 1) LIF inhibited collagen 1 and collagen 3 (Col1 and Col3) expression induced by angiotensin II (AngII) in NRK-49F (rat kidney fibroblast) cells and in unilateral ureteral obstruction (UUO) mice. 2) LIF induced Stat3 Try705 phosphorylation and inhibited Stat3 Try705 and Ser727 phosphorylation induced by AngII in NRK-49F cells. 3) LIF exerted anti-renal-fibrosis effect mainly through activating Stat3 Tyr705 phosphorylation in NRK-49F cells. These effects of LIF were not observed in Stat3-/-cells. 4). LIF-Stat3 up-regulated miR-29c expression, and the latter down-regulated Col1 and Col3 expression in NRK-49F cells and in UUO mice. In conclusion, LIF played a role in anti-renal-fibrosis by competitively activating Stat3 Try705 phosphorylation which up-regulating miR-29c to suppress collagens expression. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00634.2014
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    ABSTRACT: Editorial Focus for F-150-2015. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00287.2015
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    ABSTRACT: Diabetic nephropathy (DN) is currently a leading cause of end stage renal failure worldwide. Gremlin was identified as a gene differentially expressed in mesangial cells exposed to high glucose and in experimental diabetic kidneys. We have described that Gremlin is highly expressed in biopsies from patients with diabetic nephropathy, predominantly in areas of tubulointerstitial fibrosis. In streptozotocin (STZ)-induced experimental diabetes, Gremlin deletion using Grem1 heterozygous knockout mice or by gene silencing, ameliorates renal damage. To study the in vivo role of Gremlin in renal damage, we developed a diabetic model induced by streptozotocin (STZ) in transgenic mice expressing human Gremlin in proximal tubular epithelial cells. The albuminuria/creatinuria ratio (ACR), determined at week 20 after treatment, was significantly increased in the diabetic mice but with no significant differences between transgenic (TG/STZ) and wild type mice (WT/STZ). To assess the level of renal damage, kidney tissue was analyzed by light microscopy (PAS and Masson staining), electron microscopy and qPCR. TG/STZ mice had significant greater thickening of the glomerular basement membrane, increased mesangial matrix and podocytopenia versus WT/STZ. At the tubulointerstitial level, TG/STZ showed increased cell infiltration and mild interstitial fibrosis. In addition, we observed a decreased expression of Podocin and overexpression of MCP1 and fibrotic-related markers, including TGF-β1, Col1a1, and αSMA. Together, these results show that transgenic mice overexpressing Gremlin in renal tubules develop greater glomerular and tubulointerstitial injury in response to diabetic-mediated damage, and support the involvement of Gremlin in diabetic nephropathy. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00023.2015
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    ABSTRACT: Editorial Focus 154-2015. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00296.2015
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    ABSTRACT: The mammalian class IX myosin Myo9a is a single-headed, actin-dependent motor protein with RhoGAP (Rho GTPase activating protein) activity that negatively regulates Rho GTPase signaling. Myo9a is abundantly expressed in ciliated epithelial cells of several organs. In mice, genetic deletion of Myo9a leads to the formation of hydrocephalus. Whether Myo9a also has essential functions in the epithelia of other organs of the body has not been explored. In this study, we report that Myo9a-deficient mice develop bilateral renal disease, characterized by dilation of proximal tubules, calyceal dilation, thinning of the parenchyma and fibrosis. These structural changes are accompanied by polyuria (with normal vasopressin levels) and low molecular weight proteinuria. Immunohistochemistry revealed that Myo9a is localized to the circumferential F-actin belt of proximal tubule cells. In kidneys lacking Myo9a, the multiligand binding receptor megalin and its ligand albumin accumulated at the luminal surface of Myo9a-/- proximal tubular cells, suggesting that endocytosis is dysregulated. In addition, we found, surprisingly, that levels of the formin mDia1, a Rho effector, were decreased in Myo9a-/- kidneys, as well as in Myo9a knockdown LLC-PK1 cells. In summary, deletion of the RhoGAP Myo9a in mice causes proximal tubular dilation and fibrosis, and we speculate that downregulation of mDia1 and impaired protein reabsorption contribute to the pathophysiology. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00220.2014
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    ABSTRACT: The presence of NADPH oxidase (Nox) in the kidney, especially Nox4 (Renox), results in hydrogen peroxide (H2O2) production, which regulates sodium excretion and urine formation. Redox-sensitive transient receptor potential vanilloid 1 channels (TRPV1s) are distributed in the mechano-sensory fibers of the renal pelvis and monitor changes in intrapelvic pressure (IPP) during urine formation. This study tested whether H2O2 derived from Nox4 affects TRPV1 function in renal sensory responses. Perfusion of H2O2 into the renal pelvis dose-dependently increased afferent renal nerve activity (ARNA) and substance P (SP) release. These responses were attenuated by co-treatment with catalase or TRPV1 blockers. In single-unit recordings, H2O2 activated ARNA in response to rising IPP, but not high salt. Western blots revealed that Nox2 (gp91phox) and Nox4 are both present in rat kidney, but Nox4 is abundant in the renal pelvis and originates from dorsal root ganglia. This distribution was associated with the expression of the Nox4 regulators, p22phox and polymerase delta-interacting protein 2 (Poldip2). Co-immunoprecipitation experiments showed that IPP increases Poldip2 association with Nox4 or p22phox in the renal pelvis. Interestingly, immunofluorescence labeling demonstrated that Nox4 co-localizes with TRPV1 in the sensory fibers of the renal pelvis, indicating that H2O2 generated from Nox4 may affect TRPV1 activity. Stepwise increases in IPP and saline loading resulted in H2O2 and SP release, sensory activation, diuresis, and natriuresis. These effects, however, were remarkably attenuated by Nox inhibition. Overall, these results suggest that Nox4-positive fibers liberate H2O2 after mechano-stimulation, thereby contributing to a renal sensory nerve-mediated diuretic/natriuretic response. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00462.2014
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    ABSTRACT: Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand-supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK), and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis and activates autophagy presumably for improved cell survival. AMPK activation was diminished in the STN kidney, and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis is partially AMPK-dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00463.2014