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: Phosphatidyl-inositol-bisphosphate (PIP2) regulates epithelial sodium channel (ENaC) open probability. In turn, MARCKS protein (myristoylated alanine-rich C kinase substrate) or MARCKS-like protein 1 (MLP-1) at the plasma membrane regulates the delivery of PIP2 to ENaC. MARCKS and MLP-1 are regulated by changes in cytosolic calcium; increasing calcium promotes dissociation of MARCKS from the membrane; but the calcium regulatory mechanisms are unclear. However, it is known that increased intracellular calcium can activate calmodulin and we show that inhibition of calmodulin with calmidazolium increases ENaC activity presumably by regulating MARCKS and MLP-1. Activated calmodulin can regulate MARCKS and MLP-1 in two ways. Calmodulin can bind to the effector domain of MARCKS or MLP-1 inactivating both proteins by causing their dissociation from the membrane. Mutations in MARCKS that prevent calmodulin association prevent dissociation of MARCKS from the membrane. Calmodulin also activates CaMKinase II. An inhibitor of CaMKII (KN93) increases ENaC activity, MARCKS association with ENaC, and promotes MARCKS movement to a membrane fraction . CaMKII phosphorylates filamin. Filamin is an essential component of the cytoskeleton and promotes association of ENaC, MARCKS, and MLP-1. Disruption of the cytoskeleton with cytochalasin E reduces ENaC activity. CaMKII phosphorylation of filamin disrupts the cytoskeleton and the association of MARCKS, MLP-1, and ENaC thereby reducing ENaC open probability. Taken together, these findings suggest calmodulin and CaMKII modulate ENaC activity by destabilizing the association between the actin cytoskeleton, ENaC, and MARCKS or MLP-1 at the apical membrane. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00631.2014
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    ABSTRACT: High levels of serum uric acid or urate (SUA) is a human trait that has defied explanation. Is it beneficial? Is it pathogenic? Its role in the human diseases like gout and kidney stones was discovered over a century ago (22, 23) but today emerging new genetic and epidemiological techniques have revived an age old debate over whether high uric acid levels (hyperuricemia) independently increases risk for diseases like hypertension and chronic kidney disease (6-8, 29, 34). Part of the mystery of the role uric acid plays in human health stems from our lack of understanding of how humans regulate uric acid homeostasis, an understanding that could shed light on uric acid's historic role in human adaptation and its present role in human pathogenesis. This review will highlight the recent work to identify the first important human uric acid secretory transporter, ABCG2, and the identification of a common causal ABCG2 variant, Q141K, for hyperuricemia and gout. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00242.2015
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    ABSTRACT: The electrogenic Na+-HCO3- co-transporter 2 (NBCe2) is a newly discovered protein in the distal nephron. Our understanding is minimal regarding its physiological role in renal electrolyte transport. In this mini-review, we summarize the potential function of NBCe2 in the regulation of blood pressure, acid/base, and K+ and Ca2+ transport in the distal nephron. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 07/2015; DOI:10.1152/ajprenal.00192.2015
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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
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    ABSTRACT: The diet-induced obesity (DIO) model is frequently employed to examine the pathogenesis of obesity-related pathologies; however, only minimal glomerulosclerosis (GS) has been reported after 3 months. In the present study, we investigated if GS develops over longer periods of DIO and examined the potential role of hemodynamic mechanisms in its pathogenesis. 8-week old male obesity prone (OP) and obesity resistant (OR) rats (Charles River) were administered a moderately high fat (MHF) diet for 5 months. Radiotelemetrically-measured blood pressure (BP), proteinuria and GS were assessed. OP (n=10) rats developed modest hypertension (142±3 vs. 128±2 mmHg, P<0.05) and substantial levels of proteinuria (63±12 vs. 12±1 mg/day, P<0.05) and GS (7.7±1.4 vs. 0.4±0.2 %) vs. OR rats (n=8). Potential hemodynamic mechanisms of renal injury were assessed in additional groups of OP and OR rats fed a MHF diet for 3 months. Kidney weight (4.3±0.2 vs. 4.3±0.1 grams), glomerular filtration rate (3.3±0.3 vs. 3.1±0.1 ml/min), and glomerular volume (1.9±0.1 vs. 2.0±0.1 µm(3)x10(-6)) were similar between OP (n=6) and OR (n=9) rats. Renal blood flow (RBF) autoregulation was also similar in OP (n=7) and OR (n=7) rats. In contrast, Nω-nitro-L-arginine methyl ester (L-NAME) administration in conscious, chronically instrumented OP (n=11) rats resulted in a 15% and 39% increase in BP and renal vascular resistance, respectively, and a 16% decrease in RBF. Minimal effects of L-NAME were seen in OR (n=9) rats. In summary, DIO-associated GS is preceded by an increased hemodynamic sensitivity to L-NAME, but not renal hypertrophy or hyperfiltration. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00211.2015
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    ABSTRACT: In many circumstances, the pathogenesis of distal renal tubular acidosis (dRTA) is not understood. In the present study, we report that a mouse model lacking the electrogenic Na+-HCO3- co-transporter NBCe2/Slc4a5 (NBCe2-KO) developed dRTA after an oral acid challenge. NBCe2 expression was identified in the connecting tubule (CNT) of wild type mice (WT), and its expression was significantly increased after acid loading. NBCe2-KO did not have dRTA when on a standard mouse diet. However, after acid loading, NBCe2-KO exhibited complete features of dRTA, characterized by insufficient urinary acidification, hyperchloremic hypokalemic metabolic acidosis, and hypercalciuria. Additional experiments showed that NBCe2-KO had decreased luminal trans-epithelial voltage (Vte) in the CNT as revealed by micro-puncture. Further immunofluorescence and Western blot experiments found NBCe2-KO had increased expression of H+-ATPase B1 in the plasma membrane. These results showed that NBCe2-KO with acid loading developed increased urinary K+ and Ca2+ wasting due to the decreased luminal Vte in the CNT. NBCe2-KO compensated to maintain systemic pH by increasing H+-ATPase in the plasma membrane. Therefore, defects in NBCe2 can cause dRTA and NBCe2 has an important role to regulate urinary acidification, and the transport of K+ and Ca2+ in the distal nephron. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00163.2015
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    ABSTRACT: Despite greater understanding of acute kidney injury (AKI) in animals models, many of the preclinical studies are not translatable. Most of the data were derived from a bilateral renal pedicle clamping model with warm ischemia. However, ischemic injury of the kidney in human is distinctly different and does not involve clamping of renal vessel. Using permanent ligation of the left anterior descending coronary artery model to test the role of miR-150 in acute kidney injury. Myocardial infarction in this model causes AKI which is similar to human cardiac bypass surgery. Moreover, the time course of serum creatinine and biomarker elevation were also similar to human ischemic injury. Deletion of miR-150 suppressed AKI which was associated with suppression of inflammation and interstitial cell apoptosis. Immunofluorescence staining with endothelial marker and marker of apoptosis suggested that dying cells are mostly endothelial cells with minimal epithelial cell apoptosis in this model. Interestingly, deletion of miR-150 also suppressed interstitial fibrosis. Consistent with protection, miR-150 deletion causes induction of its target gene IGF-1R and overexpression of miR-150 in endothelial cells downregulated IGF-1R suggesting miR-150 may mediate its detrimental effects through suppression of IGF-1R pathways. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00076.2015
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    ABSTRACT: Because cyclophosphamide-induced hyponatremia was reported to occur without changes in plasma vasopressin in a patient with central diabetes insipidus, we hypothesized that cyclophosphamide or its active metabolite, 4-hydroperoxycyclophosphamide (4-HC), may directly dysregulate the expression of water channels or sodium transporters in the kidney. To investigate whether intrarenal mechanisms for urinary concentration are activated in vivo and in vitro by treatment with cyclophosphamide and 4-HC, respectively, we used water-loaded male Sprague-Dawley rats, primary cultured inner medullary collecting duct (IMCD) cells, and IMCD suspensions prepared from male Sprague-Dawley rats. In cyclophosphamide-treated rats, significant increases in renal expression of aquaporin-2 (AQP2) and Na-K-2Cl cotransporter type 2 (NKCC2) were shown by immunoblot analysis and immunohistochemistry. Apical translocation of AQP2 was also demonstrated by quantitative immunocytochemistry. In both rat kidney and primary cultured IMCD cells, significant increases in AQP2 and vasopressin receptor type 2 (V2R) mRNA expression were demonstrated by real-time quantitative PCR analysis. Confocal laser scanning microscopy revealed that apical translocation of AQP2 was remarkably increased when primary cultured IMCD cells were treated with 4-HC in the absence of vasopressin stimulation. Moreover, AQP2 upregulation and cAMP accumulation in response to 4-HC were significantly reduced by tolvaptan co-treatment in primary cultured IMCD cells and IMCD suspensions, respectively. We demonstrated that, in the rat kidney, cyclophosphamide may activate V2R and induce upregulation of AQP2 in the absence of vasopressin stimulation, suggesting the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00477.2014
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    ABSTRACT: Ketamine abusers develop severe lower urinary tract symptoms. The major aims of our study were to elucidate ketamine-induced ulcerative cystitis and bladder apoptosis in association with oxidative stress mediated by mitochondria and endoplasmic reticulum (ER). Sprague-Dawley rats were distributed into three different groups, which received saline, or ketamine for a period of 14 days or 28 days, respectively. The double-labeled immunofluorescence studies were applied to investigate tight junction proteins for urothelial barrier functions. The terminal deoxynucleotidyl transferase dUTP nick-end labeling assay was performed to evaluate the distribution of apoptotic cells. Western blot was carried out to examine the expressions of urothelial tight junction proteins, ER stress markers, and apoptosis-associated proteins. The antioxidant enzymes, including superoxide dismutase and catalase, were investigated by real time PCR and immunofluorescence studies. The ketamine-treated rats were found to display bladder hyperactivity. Such bladder dysfunction were accompanied by the disruptions of epithelial-cadherin and tight-junction-associated proteins as well as increases in the expressions of apoptosis-associated proteins, which displayed the features of mitochondria-dependent apoptotic signals, and ER stress markers. Meanwhile, the expressions of mitochondria respiratory subunits enzymes were significantly increased in ketamine-treated bladder. Conversely, the mRNA expressions of antioxidant enzymes Mn-SOD, Cu/Zn-SOD and catalase were also decreased after 28 days ketamine treatment. Ketamine enhances the generation of oxidative stress mediated by mitochondria- and ER-dependent pathways, and consequently attributed to bladder apoptosis and urothelial lining defects. Such oxidative stress-enhanced bladder cell apoptosis and urothelial barrier defects are potential factors that may play crucial role in bladder over-activity and ulceration. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00607.2014
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    ABSTRACT: The role of the non-gastric H(+)/K(+) ATPase (HKA) in ion homeostasis of macula densa (MD) cells is an open question. To begin to explore this issue, we developed two mathematical models that describe the ion fluxes through a non-gastric HKA. One model assumes a 1H(+):1K(+)-per-ATP stoichiometry; the other assumes a 2H(+):2K(+)-per-ATP stoichiometry. Both models include Na(+) and NH4 (+) competitive binding with H(+) and K(+), respectively, a characteristic observed in vitro and in situ. Model rate constants were obtained by minimizing the distance between model and experimental outcomes. Both models, 1H(+)(1Na(+)):1K(+)(1NH4 (+))-per-ATP and 2H(+)(2Na(+)):2K(+)(2NH4 (+))-per-ATP, fit well the experimental data. Using both models, we simulated the ion net fluxes as a function of cytosolic or luminal ion concentrations typical for the cortical thick ascending limb and MD region. We observed that: K(+) and NH4 (+) flowed in the lumen-to-cytosol direction; there was competitive behavior between luminal K(+) and NH4 (+) and between cytosolic Na(+) and H(+); ion fluxes were highly sensitive to changes in cytosolic [Na(+)] or [H(+)]; the transporter does mostly Na(+)/K(+) exchange under physiological conditions. These results support the concept that the non-gastric HKA may contribute to Na(+) and pH homeostasis in MD cells. Furthermore, in both models H(+) flux reversed at a luminal pH that is less than 5.6. Such reversal led to Na(+)/H(+) exchange for luminal pH less than 2 and 4 in the 1:1- and 2:2-per-ATP models, respectively. This suggests a novel role of the non-gastric HKA in cell Na(+) homeostasis in the more acidic regions of the renal tubules. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00539.2014
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    ABSTRACT: editorial F-138-2015. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00237.2015
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    ABSTRACT: Podocytes (terminally differentiated epithelial cells of the glomeruli) play a key role in the maintenance of glomerular structure and permeability and in the incipiency of various renal abnormalities. Injury to podocytes is considered a major contributor to the development of the kidney disease as their loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium handling; excessive calcium influx in these cells may result in foot processes effacement, apoptosis and subsequent glomeruli damage. One of the key proteins responsible for calcium flux in the podocytes is TRCP6 (transient receptor potential cation channel, subfamily C, member 6) channel; a gain-of-function mutation in TRPC6 has been associated with the onset of the familial forms of focal segmental glomerulosclerosis (FSGS). Recent data also revealed a critical role of this channel in the onset of diabetic nephropathy. Therefore, major efforts of the research community have been recently dedicated to unraveling the TRPC6-dependent effects in the initiation of the podocyte injury. This mini-review focuses on the TRPC6 channel in podocytes and colligates recent data in attempt to shed some light on the mechanisms underlying the pathogenesis of TRPC6-mediated glomeruli diseases and its potential role as therapeutic target for the treatment of chronic kidney diseases. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00186.2015
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    ABSTRACT: During metabolic acidosis, the cortical collecting duct (CCD) of the rabbit reverses the polarity of bicarbonate flux from net secretion to net absorption, and this is accomplished by increasing the proton secretory rate by α-intercalated cells (α-ICs) and decreasing bicarbonate secretion by β-ICs. To better characterize dynamic changes in H(+)-secreting α-ICs we examined their morphology in collecting ducts microdissected from kidneys of normal, acidotic, and recovering rabbits. α-ICs in defined axial regions varied in number and basolateral anion exchanger 1 (AE1) morphology which likely reflects their relative activity and function along the collecting duct. Upon transition from CCD to outer medullary collecting duct from the outer stripe (OMCDo) to inner stripe (OMCDi), the number of α-ICs increases from 11.0±1.2 to 15.4±1.11, and to 32.0±1.3 cells/200 microns, respectively. In the CCD the basolateral structure defined by AE1 typically exhibited a pyramidal or conical shape, whereas in the medulla the morphology was elongated and shallow resulting in a more rectangular shape. Furthermore, acidosis reversibly induced α-ICs in the CCD to acquire a more rectangular morphology concomitant with a transition from diffusely cytoplasmic to increased basolateral surface distribution of AE1 and apical polarization of B1-V-ATPase. The latter results are consistent with the supposition that morphological adaptation from the pyramidal to the rectangular shape reflects a transition toward a more "active" configuration. In addition, α-ICs in OMCDo exhibited cellular morphology strikingly similar to dendritic cells that may reflect a newly defined ancillary function in immune defense of the kidney. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00161.2015
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    ABSTRACT: AKI is a common hospital complication. There are no effective treatments to minimize kidney injury or limit associated morbidity and mortality. Currently, serum creatinine and urine output remain the gold standard used clinically in the diagnosis of AKI. Several novel biomarkers can diagnose AKI earlier than elevations of serum creatinine and changes in urine output. Recent long term observational studies have elucidated a sub-group of patients who have positive biomarkers of AKI but do not meet criteria for AKI by serum creatinine or urine output, termed subclinical AKI. These patients with subclinical AKI have increased risk of both short and long-term mortality. In this review we will highlight the implications of what these patients may represent and the need for better phenotyping of AKI by etiology, severity of injury and ability to recover. We will discuss two AKI biomarkers, NGAL and BRP-39/YKL-40, that exemplify the need to characterize the complexity of the biologic meaning behind the biomarker, beyond elevated levels reporting on tissue injury. Ultimately, careful phenotyping of AKI will lead to identification of therapeutic targets and appropriate patient populations for clinical trials. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00682.2014
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    ABSTRACT: Severe defects in the glomerular filtration barrier result in nephrotic syndrome, which is characterized by massive proteinuria. The podocyte, a specialized epithelial cell with interdigitating foot processes separated by a slit diaphragm, plays a vital role in regulating the passage of proteins from the capillary lumen to Bowman's space. Recent findings suggest a critical role for endocytosis in podocyte biology as highlighted by genetic mouse models of disease and human genetic mutations that result in the loss of the integrity of the glomerular filtration barrier. In-vitro podocyte studies have also unraveled a plethora of constituents that are differentially internalized to maintain homeostasis. These observations provide a framework and impetus for understanding the precise regulation of podocyte endocytic machinery during both health and disease. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00136.2015
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    ABSTRACT: High sodium intake is a risk factor for the pathogenesis of hypertension, especially in obesity. The present study is designed to investigate whether angiotensin type-2 receptor activation with selective agonist C21 prevents high-sodium diet (HSD)-induced hypertension in obese animals. Male obese rats were treated with AT2R agonist C21 (1 mg/kg/day, oral) while maintained on either normal-sodium diet (NSD, 0.4%) or HSD (4%) for 2-weeks. Radio-telemetric recording showed a time dependent increase in systolic blood pressure in HSD-fed obese rats, being maximal increase (~27 mmHg) at day 12 of the HSD regimen. C21 treatment completely prevented the increase in blood pressure of HSD-fed rats. Compared to NSD controls, HSD-fed obese rats had greater natriuresis/diuresis and urinary levels of nitrates, and these parameters were further increased by C21 treatment. HSD-fed rats expressed higher level of cortical AngII, which was reduced to 50% by C21 treatment. HSD feeding and/or C21 treatment had no effects on cortical renin activity and the expression of angiotensin converting enzyme and chymase, which are AngII producing enzymes. However, Ang(1-7) concentration and ACE2 activity in the renal cortex were reduced by HSD feeding, and C21 treatment rescued both the parameters. Also, C21 treatment reduced the cortical expression of AT1R in HSD-fed rats, but had no effect of AT2R expression. We conclude that chronic treatment with the AT2R agonist C21 prevents salt-sensitive hypertension in obese rats, and a reduction in the renal AngII/AT1R and enhanced ACE2/Ang(1-7) levels may play a potential role in this phenomenon. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; 308(12). DOI:10.1152/ajprenal.00002.2015
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    ABSTRACT: The goal of this study was to quantify and correlate the contribution of the cytosolic p67phox subunit of NADPH-oxidase2 (Nox2) to mitochondrial oxidative stress in the kidneys of the Dahl salt-sensitive (SS) hypertensive rat. Whole kidney redox states were uniquely assessed using a custom designed optical fluorescence 3D cryoimager to acquire multi-channel signals of the intrinsic fluorophores NADH and FAD. SS rats were compared to SS rats in which the cytosolic subunit p67phox was rendered functionally inactive by zinc fingered nuclease mutation of the gene (SS(p67phox) null rats). Kidneys of SS rats fed 0.4% NaCl diet exhibited significantly (p=0.023) lower tissue redox ratio (NADH/FAD) (1.42±0.06; n=5) than SS(p67phox) null rats (1.64±0.07; n=5), indicating reduced levels of mitochondrial electron transport chain metabolic activity and enhanced oxidative stress in SS rats. When fed 4.0% salt diet for 21 days both strains exhibited significantly lower tissue redox ratios (p<0.001; SS 1.03±0.05, n=9 vs SS(p67phox) 1.46±0.04, n=7) than when fed 0.4% salt but the ratio was still significantly higher in the SS(p67phox) rats at the same salt level as the SS. These results are consistent with results from previous studies that found elevated medullary interstitial fluid concentrations of superoxide and H2O2 in the medulla of SS rats. We conclude that the p67phox subunit of Nox2 plays an important role in the excess production of ROS from mitochondria in the renal medulla of the SS rat. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    AJP Renal Physiology 06/2015; DOI:10.1152/ajprenal.00098.2015