AJP Renal Physiology (Am J Physiol Ren Physiol )

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


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.

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  • Cited half-life
  • Immediacy index
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  • Website
    American Journal of Physiology - Renal Physiology website
  • Other titles
    American journal of physiology., Renal physiology, Renal physiology, AJP: renal physiology
  • ISSN
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  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

American Physical Society

  • Pre-print
    • Author cannot archive a pre-print version
  • Restrictions
    • Journal of Neurophysiology only (until February 2011)
  • Post-print
    • Author cannot archive a post-print version
  • Conditions
    • NIH funded authors, may archive papers in PubMed Central after 12 months
    • Wellcome Trust authors may use Paid Option to archive in PubMed Central
    • Authors are requested to notify publisher of funding source at time of submission and to modify copyright statement to indicate time of release in PubMed
    • Journal of Neurophysiology only - pre-print only before submission
    • Journal of Neurophysiology only - pre-print on preprint server or non peer reviewed websites
    • Journal of Neurophysiology only - pre-print must not be revised
    • Publisher's version/PDF cannot be used
  • Classification
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiotensin II (Ang II) acting through its type 1 (AT1) receptor stimulates total ammonia (tNH3) production by the proximal tubule. The present studies explored the role of Ang II type 2 (AT2) receptors in modulating the stimulatory effects of Ang II on tNH3 production. Mouse S2 proximal tubule segments derived from 18-h and 7-d acid loaded mice, and non-acid-loaded controls were dissected and microperfused in vitro. Adding Ang II to the luminal perfusion solution resulted in different increments in tNH3 production rates in tubules derived from 18-h versus 7-d acid-loaded mice such that the increase in tNH3 production with Ang II was higher in tubules derived from 18-h acid-loaded mice compared to those derived from control and 7-d acid-loaded mice. Adding the AT2 receptor blocker PD123319 with Ang II increased Ang II-stimulated tNH3 production in S2 segments from control and 7-d acid-loaded mice but not in those from 18-h acid-loaded mice and this increased effect of PD123319 was associated with higher AT2 receptor protein levels in brush border membranes. Studies on cultured proximal tubule cells demonstrated that 2-h exposure to pH 7.0 reduced the modulating effect of PD123319 on Ang II-simulated tNH3 production and reduced cell surface AT2 receptor levels. We concluded that AT2 receptors reduce the stimulatory effect of Ang II on proximal tubule tNH3 production and that the time-dependent impact of AT2 receptor blockade on the Ang II-stimulated tNH3 production corresponded to time-dependent changes in AT2 receptor cell surface expression in the proximal tubule.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Betaine is an important osmolyte and is, compared to other organs, much more abundant in the kidneys where it enters cells in the medulla by the Betaine-GABA-Transporter 1 (BGT1) to balance osmoregulation in the counter current system. In wildtype BGT1 (wt-BGT1)-expressing oocytes, GABA-mediated currents were diminished by preincubation of the oocytes with 100 nM PMA or 5 µM DOG, activators of the protein kinase C (PKC), while application of staurosporine prior to application of DOG restored the response to GABA. Four potential phosphorylation sites on BGT1 were mutated to alanine by site-directed mutagenesis. Three mutants (T235A, S428A, and S564A) evoked GABA currents comparable in magnitude to the currents observed in wt-BGT1-expressing oocytes, whereas GABA currents in T40A were barely detectable. Uptake of [3H]GABA was also determined in HEK293 cells expressing EGFP-tagged BGT1 with the same mutations. T235A, S428A, and S564A showed up-regulation of GABA uptake after hypertonic stress and down-regulation by PMA similar to EGFP-wt-BGT1. In contrast T40A did not respond to either hypertonicity or PMA. Confocal microscopy of the EGFP-BGT1 mutants expressed in MDCK cells revealed that T40A was present in cytoplasm after 24 hours of hypertonic stress while the other mutants and EGFP-wt-BGT1 were in the plasma membrane. All mutants, including T40A, co-migrated with wt-BGT1 on Western blots suggesting that they are full length proteins. T40A, however, cannot be phosphorylated as revealed using a specific anti-phospho antibody and therefore T40 may be important for trafficking and insertion of BGT1 in the plasma membrane.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Efficient clearance of apoptotic cells (efferocytosis) prevents inflammation and permits repair following tissue injury. Kidney injury molecule-1 (KIM-1) is a receptor for phosphatidylserine, an "eat me" signal exposed on the surface of apoptotic cells that marks them for phagocytic clearance. KIM-1 is upregulated on proximal tubule epithelial cells (PTECs) during ischemic acute kidney injury (AKI), enabling efferocytosis by surviving PTECs. KIM-1 is spontaneously cleaved at its ectodomain region to generate a soluble fragment that serves a sensitive and specific biomarker for AKI, but the biological relevance of KIM-1 shedding is unknown. Here, we sought to determine how KIM-1 shedding might regulate efferocytosis. Using cells that endogenously and exogenously express KIM-1 we found that hydrogen peroxide-mediated oxidative injury or phorbol-12-myristate-13-acetate (PMA) treatment accelerated KIM-1 shedding in a dose-dependent manner. KIM-1 shedding was also accelerated when apoptotic cells were added. Accelerated shedding or the presence of excess soluble KIM-1 in the extracellular milieu significantly inhibited efferocytosis. We identified that tumor necrosis factor alpha-converting enzyme (TACE or ADAM17) mediates both the spontaneous and PMA-accelerated shedding of KIM-1. While accelerated shedding inhibited efferocytosis, we found that spontaneous KIM-1 cleavage does not affect the phagocytic efficiency of PTECs. Our results suggest that KIM-1 shedding is accelerated by worsening cellular injury and excess soluble KIM-1 competitively inhibits efferocytosis. These findings may be important in AKI when there is severe cellular injury.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Numerous reports have linked cytoskeleton associated proteins with the regulation of ENaC activity. The purpose of this study was to determine the effect of actin cytoskeleton disruption by cytochalasin E on ENaC activity in Xenopus 2F3 cells. Here we show cytochalasin E treatment for 60 minutes can disrupt the integrity of the actin cytoskeleton in cultured Xenopus 2F3 cells. We show by single-channel patch clamp studies and measurements of short circuit current that ENaC activity, but not its density is altered by cytochalasin E induced disruption of the cytoskeleton. In non-treated cells 8 out of 33 patches (24%) had no measurable ENaC activity while in cytochalasin E treated cells 17 out of 32 patches (53%) had no activity. Analysis of those patches that did contain ENaC activity showed channel open probability significantly decreased from 0.081 ± 0.01 in non-treated cells to 0.043 ± 0.01 in cells treated with cytochalasin E. Transepithelial current from mpkCCD cells treated with cytochalasin E, cytochalasin D, or latrunculin B for 60 minutes was decreased compared to vehicle treated cells. The subcellular expression of fodrin changed significantly and several protein elements of the cytoskeleton decreased at least two fold after 60 minutes of cytochalasin E treatment. Cytochalasin E treatment disrupted the association between ENaC and MARCKS. The results presented here suggest disruption of the actin cytoskeleton by different compounds can attenuate ENaC activity through a mechanism involving changes in the subcellular expression of fodrin, several elements of the cytoskeleton, and destabilization of the ENaC-MARCKS complex.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Energy depletion increases the renal production of 2',3'-cAMP (a positional isomer of 3',5'-cAMP that opens mitochondrial permeability transition pores) and 2',3'-cAMP is converted to 2'-AMP and 3'-AMP, which in turn are metabolized to adenosine. Because the enzymes involved in this "2',3'-cAMP-adenosine pathway" are unknown, we examined whether 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) participates in the renal metabolism of 2',3'-cAMP. Western blotting and real time PCR demonstrated expression of CNPase in rat glomerular mesangial, preglomerular vascular smooth muscle and endothelial, proximal tubular, thick ascending limb and collecting duct cells. Real time PCR established the expression of CNPase in human glomerular mesangial, proximal tubular and vascular smooth muscle cells; and the level of expression of CNPase was greater than that for phosphodiesterase 4 (major enzyme for the metabolism of 3',5'-cAMP). Over-expression of CNPase in rat preglomerular vascular smooth muscle cells increased the metabolism of exogenous 2',3'-cAMP to 2'-AMP. Infusions of 2',3'-cAMP into isolated CNPase wildtype (+/+) kidneys increased renal venous 2'-AMP, and this response was diminished by 63% in CNPase knockout (-/-) kidneys; whereas the conversion of 3',5'-cAMP to 5'-AMP was similar in CNPase +/+ versus -/- kidneys. In CNPase +/+ kidneys, energy depletion (metabolic poisons) increased kidney tissue levels of adenosine and its metabolites (inosine, hypoxanthine, xanthine and uric acid) without accumulation of 2',3'-cAMP. In contrast, in CNPase -/- kidneys, energy depletion increased kidney tissue levels of 2',3'-cAMP and abolished the increase in adenosine and its metabolites. Conclusion: Kidneys express CNPase, and renal CNPase mediates in part the renal 2',3'-cAMP-adenosine pathway. Key Words: 2',3'-cyclic adenosine monophosphate; 2'-adenosine monophosphate; 3'-adenosine monophosphate; adenosine; 2',3'-cyclic nucleotide 3'-phosphodiesterase; CNPase.
    AJP Renal Physiology 05/2014; 307:F14-F24.
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    ABSTRACT: Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to increased risk of cardiovascular death in CKD. However, the effects of Pi overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary phosphate loading on the interaction among inflammation, malnutrition and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different phosphate concentrations ranging from 0.3% to 1.2% for 8 weeks. CKD rats showed dietary phosphate concentration-dependent increases in serum and tissue levels of tumor necrosis factor-α, and urinary and tissue levels of oxidative stress markers, and developed malnutrition (decrease in body weight, serum albumin and urinary creatinine excretion), VC and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by phosphate overload. Regression analysis showed that serum phosphate levels closely correlated with the extent of inflammation, malnutrition and VC. Also, in cultured human vascular smooth muscle cells, high-phosphate medium directly increased the expression of tumor necrosis factor-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary phosphate overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and inhibition of phosphate loading through dietary or pharmacological interventions, or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: The intrarenal dopamine system is important for signaling and natriuresis, and significant dysfunction is associated with hypertension and kidney disease in ex vivo studies. Dopamine receptors also modulate and are modulated by the renin-angiotensin-aldosterone system (RAAS). Here we show the first in vivo measurement of D1-like receptors in the renal cortex of Sprague Dawley rat and Papio anubis baboon using [(11)C]NNC 112, a positron emission tomography (PET) radioligand for D1-like receptors. In addition we show a D1-like binding potential response to angiotensin II blockade in rat using losartan. Demonstration of self-saturable binding in the rat as well as specific and saturable binding in Papio anubis validate the use of [(11)C]NNC 112 in the first in vivo measurement of renal dopamine D1-like receptors. Furthermore, [(11)C]NNC 112 is a radioligand tool already validated for use probing human central nervous system D1-like receptors. Our work demonstrates specific and saturable non-CNS binding in higher animals and the ability to quantify physiological response to drug treatment and provides a clear path to extend use of [(11)C]NNC 112 to study renal dopamine in humans.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Adriamycin (ADR)-induced nephropathy in animals is an experimental analogue of human focal segmental glomerulosclerosis (FSGS), which presents as severe podocyte injury and massive proteinuria and has a poorly understood mechanism. The current study was designed to test the hypothesis that the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)/mitochondria axis is involved in ADR-induced podocyte injury. Using MPC5 immortalized mouse podocytes, the ADR dose-dependently induced the downregulation of nephrin and podocin, cell apoptosis, and mitochondrial dysfunction based on the increase in mitochondrial reactive oxygen species (ROS) production, a decrease in mitochondrial DNA (mtDNA) copy number, and the reduction of mitochondrial membrane potential (MMP) and ATP content. Moreover, ADR treatment also remarkably reduced the expression of PGC-1α, an important regulator of mitochondrial biogenesis and function, in podocytes. Strikingly, PGC-1α overexpression markedly attenuated mitochondrial dysfunction, reduction of nephrin and podocin, and the apoptotic response in podocytes following ADR treatment. Moreover, the downregulation of PGC-1α and mitochondria disruption in podocytes were also observed in rat kidneys with ADR administration, suggesting that the PGC-1α/mitochondria axis is relevant to the in vivo ADR-induced podocyte damage. Taken together, these novel findings suggest that dysfunction of the PGC-1α/mitochondria axis is highly involved in ADR-induced podocyte injury. Targeting PGC-1α may be a novel strategy for treating ADR nephropathy and FSGS disease.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: editorial focus F-585-2013.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Enhanced tubular reabsorption of salt is important in the pathogenesis of obesity-related hypertension but the mechanisms remain poorly defined. To identify changes in regulation of salt transporters in the kidney, C57BL/6 mice were fed 40% (high fat, HFD) or 12% (control, CD) fat diets for 14 weeks. Compared with controls, HFD mice had significantly greater elevations in weight, blood pressure, and serum insulin and leptin levels. Examining sodium transporter expression, NKCC2 was unchanged in whole kidney and reduced in the cortex; NCC and α- and γ-ENaC were unchanged; β-ENaC was reduced. Phosphorylation of NCC was unaltered. Activating phosphorylation of NKCC2 at S126 was increased 2.5-fold. Activation of SPAK/OSR-1 was increased in kidneys from HFD mice and enhanced phosphorylation of NKCC2 at T96/T101 was evident in the cortex. Increased activity of NKCC2 in vivo was confirmed with diuretic studies. HFD mice had reduced activating phosphorylation of AMPK in the renal cortex. In vitro, activation of AMPK led to a reduction in pSPAK/pOSR1 in MEF-AMPK(+/+) cells, but no effect was seen in MEF-AMPK-/- cells, indicating an AMPK-mediated effect. Activation of the WNK/SPAK/OSR1 pathway with low sodium chloride solution invoked a greater elevation in pSPAK/pOSR1 in MEF-AMPK(-/-) cells than MEF-AMPK(+/+) cells, consistent with a negative regulatory effect of AMPK on SPAK/OSR1 phosphorylation. In conclusion, this study identifies increased phosphorylation of NKCC2 on S126 as a hitherto unrecognized mediator of enhanced sodium reabsorption in obesity, and identifies a new role for AMPK in regulating the activity of SPAK/OSR1.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased NGAL expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Further, renal EGFR signaling is subject to regulation by this class of HDACs.
    AJP Renal Physiology 05/2014;
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    ABSTRACT: Various animal models have been used in research into bladder dysfunction, and in vivo cystometry is a common method to analyze bladder function in animals. However, it is rather difficult to perform reliably in small animals. Transabdominal bladder ultrasonography combined with cystometry in urethane-anesthetized mice have revealed physical inhibition of bladder wall movement by a bladder catheter conventionally placed in the bladder apex. For reliable evaluation of mouse lower urinary tract function, we established a novel cystometry method in which a catheter was placed in the bladder anterior wall, in combination with bladder ultrasonography. This new method allowed the bladder to be well distended, (i.e., larger maximum bladder capacity, lower pressure threshold, higher voided volume and higher bladder compliance compared with conventional methods), which reflected more spontaneous voiding than conventional cystometry methods. We also demonstrated the usefulness of bladder ultrasonography for analysis of mouse bladder function, especially bladder dynamics, maximum bladder capacity and post-voiding residual volume. We analyzed bladder functional changes in lipopolysaccharide (LPS)-induced cystitis by combining bladder ultrasonography and this new cystometry method. Bladder ultrasonography revealed a rapid decrease in bladder capacity, and cystometry showed rapid decrease of voided volume due to intravesical LPS instillation. This new cystometry method also revealed a rapid decrease in bladder compliance caused by LPS instillation, which was not detectable by conventional methods. The combination of ultrasonography and new cystometry method may become a powerful tool for analysis of mouse bladder function and could contribute to the development of new treatments for bladder dysfunction.
    AJP Renal Physiology 05/2014;
  • AJP Renal Physiology 05/2014; 306(9):F1098-F1100.
  • AJP Renal Physiology 05/2014; 306(9):F1101-F1103.
  • AJP Renal Physiology 05/2014; 306(9):F1104-F1105.
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    ABSTRACT: LMX1B is a transcription factor of the LIM-homeodomain type and is implicated in the development of diverse structures such as limbs, kidneys, eyes and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30% of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and renal interstitial fibrosis, we explored if LMX1B affects typical markers of fibrosis, e.g., extracellular matrix components, profibrotic factors, and apoptosis as the final detrimental consequence. We recently showed that LMX1B acts as a negative regulator of transforming growth factor-βl, collagen-III, fibronectin, cleaved caspase-3, and cell apoptosis rate in a renal tubular epithelial cell system under hypoxic conditions. Here we confirmed these results in unilateral ureteral obstructed rats. Furthermore, LMX1B was distinctly expressed throughout the glomerulus and the tubule lining, including the epithelial cells. Knockdown of LMX1B aggravated the expression of fibrosis markers, oxidative stress, and apoptosis compared with the already increased levels due to unilateral ureteral obstruction, whereas overexpression attenuated these effects. In conclusion, reduced LMX1B levels clearly represent a risk factor for renal fibrosis, whereas overexpression affords some level of protection. In general, LMX1B may be considered to be a negative regulator of the fibrosis index, transforming growth factor-βl, collagen-III, fibronectin, cleaved caspase-3, cell apoptosis, reactive oxygen species and malon dialdehyde (r= -0.756, -0.698, -0.921, -0.923, -0.843, -0.794, -0.883, -0.825; each P<0.01).
    AJP Renal Physiology 04/2014;
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    ABSTRACT: The amount of sodium and potassium in the diet promotes significant changes in endothelial cell function. In the present study, a series of in vitro and in vivo experiments determined the role of sodium and potassium in the regulation of two Pleckstrin Homology domain-containing intracellular signaling molecules - phospholipase C gamma-1 (PLCγ-1) and Epithelial and endothelial tyrosine kinase/Bone marrow tyrosine kinase on chromosome X (Bmx) - and agonist-generated calcium signaling in the endothelium. Extracellular [K(+)] regulated the levels of activated PLCγ-1, Bmx and carbachol-stimulated intracellular Ca(2+) mobilization in human endothelial cells. Additional experiments confirmed that high-conductance calcium-activated potassium channels and phosphatidylinositol 3-kinase mediated these effects. The content of sodium and potassium in the diet also regulated Bmx levels in endothelial cell and activated PLCγ-1 levels in rats in vivo. The effects of dietary potassium on Bmx was more pronounced in rats on the high-salt diet, compared to rats on the low-salt diet. These studies elucidated an endothelial cell signaling mechanism regulated by electrolytes, further demonstrating an integral relationship between endothelial cell function and dietary sodium and potassium content.
    AJP Renal Physiology 04/2014;

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