American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Effects of proximal tubule NBCe1-A deletion on collecting duct intercalated cell responses to hypokalemia.
Lee HW, Harris AN, Wall SM … +1 more , Weiner ID
Am J Physiol Renal Physiol · 2026 Jul · PMID 42160474 · Full text
Hypokalemia activates intercalated cell acid secretion, but because hypokalemia is typically associated with metabolic alkalosis, this activation cannot be ascribed to extracellular pH. Metabolic acidosis induces respons...
Hypokalemia activates intercalated cell acid secretion, but because hypokalemia is typically associated with metabolic alkalosis, this activation cannot be ascribed to extracellular pH. Metabolic acidosis induces responses similar to those of hypokalemia, and its effects are blocked by deletion of the proximal tubule Na-bicarbonate cotransporter, electrogenic, isoform 1, variant A (NBCe1-A). This response likely involves ammonia: metabolic acidosis stimulates ammoniagenesis through an NBCe1-A-dependent mechanism, and ammonia stimulates collecting duct acid secretion. Since hypokalemia also stimulates ammoniagenesis through an NBCe1-A-dependent mechanism, we postulated that a similar proximal tubule NBCe1-A-dependent mechanism underlies hypokalemia's effect on collecting duct intercalated cells. To test this, we induced hypokalemia by providing a nominally K-free diet for 4 days to wild-type (WT) and NBCe1-A deletion (KO) mice. Hypokalemia increased % of cortical collecting duct (CCD) type A intercalated cells (A-cells), decreased % of CCD type B intercalated cells (B-cells), increased cortical anion exchanger 1 (AE1) expression, increased % of A-cells in the inner stripe of the outer medullary collecting duct (OMCD), increased OMCD A-cell height, increased apical polarization of OMCD A-cell H-ATPase, and increased OMCD AE1 expression. NBCe1-A deletion inhibited each of these responses. Hypokalemia reduced B-cell pendrin abundance; this was NBCe1-A-independent, whereas the reduction to metabolic acidosis was NBCe1-A-dependent in a previous study. We conclude that the proximal tubule, through an NBCe1-A-dependent mechanism likely involving ammonia, regulates the A-cell acid-secretory response to hypokalemia. Because a similar paradigm is present in the response to metabolic acidosis, this may represent a generalized pathway regulating collecting duct acid secretion. The collecting duct response to hypokalemia is not innate to the collecting duct, which is paradoxical from an acid-base perspective, and instead requires proximal tubule-dependent NBCe1-A-dependent signaling to occur.
Arteriovenous fistula creation results in cardiac dysfunction and remodeling in a uremic pig model.
Kane J, Singh PG, Kilari S … +10 more , Baranwal G, Roy-Chowdhury S, Naskar A, Montonye D, Lutgens E, Wang Y, Negm AS, Collins JD, Lee T, Misra S
Am J Physiol Renal Physiol · 2026 Jun · PMID 42154641 · Publisher ↗
The arteriovenous fistula (AVF) is required for hemodialysis in end-stage kidney disease (ESKD). AVF creation results in compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling...
The arteriovenous fistula (AVF) is required for hemodialysis in end-stage kidney disease (ESKD). AVF creation results in compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling. Relatedly, cardiovascular mortality and morbidity are elevated in patients with ESKD, which worsens in patients with dialysis. Currently, no suitable uremic large animal models exist to investigate the mechanisms of AVF-induced cardiac remodeling. This study aims to characterize cardiovascular changes secondary to AVF creation, supported by percutaneous transluminal angioplasty (PTA), in a uremic pig model. Chronic kidney disease (CKD) was induced via renal embolization, followed by AVF creation 28 days later. AVF stenosis was alleviated 28 days thereafter via PTA, and cardiac magnetic resonance imaging (MRI) was performed at 14, 28, and 42 days post-PTA. Increased end-diastolic volumes were observed in both ventricles, whereas systolic function was preserved. Left ventricular (LV) stroke volume and blood flow through the aorta, pulmonary artery, and vena cava were also increased. In perivascular areas of the LV, senescence markers showed increased p16 expression and decreased p21 expression. The LV showed perivascular fibrosis, with increased cardiomyocyte cross-sectional area, reduced collagen-type IV expression, and matrix metalloproteinase 2 (MMP2) activity, possibly not driven by transforming growth factor-β (TGF-β)/connective tissue growth factor (CTGF)/phosphorylated SMAD signaling. However, CD4 or CD68 cell LV infiltration and inflammatory polarization of resident macrophages were unchanged. In conclusion, AVF creation modified left and right ventricular function and increased peripheral flow, potentially mediated by cellular senescence and fibrosis, resulting in progressive cardiac remodeling. This model may be used to evaluate mechanisms of AVF-induced cardiac disease and potentially investigate the efficacy of senolytics and antifibrotic agents. The creation of an arteriovenous fistula in a uremic pig induces cardiac remodeling, which resembles contemporary clinical findings in patients with end-stage kidney disease (ESKD) and includes increased end-diastolic volumes and cardiomyocyte hypertrophy, potentially driven by fibrosis and senescence. This novel large animal model may now enable mechanistic and therapeutic studies aiming to ease the unacceptably high burden of cardiovascular disease on patients with ESKD.
Diurnal and sex-specific renal responses to vasopressin receptor 2 agonism and antagonism in mice.
Nguyen H, Huynh NV, Hyndman KA
Am J Physiol Renal Physiol · 2026 Jun · PMID 42132436 · Publisher ↗
Renal function in humans and rodents displays a clear circadian pattern with greater glomerular filtration and excretion during the active period. Arginine vasopressin (AVP) regulates water balance primarily through the...
Renal function in humans and rodents displays a clear circadian pattern with greater glomerular filtration and excretion during the active period. Arginine vasopressin (AVP) regulates water balance primarily through the vasopressin receptor 2 (V2R). Although both V2R agonists and antagonists are used clinically, it remains unclear whether their efficacy varies by the time of day. Because mRNA expression is greater during the active phase in mice, we hypothesized that V2R agonism and antagonism would produce diurnal effects on urine-concentrating responses. Adult male and female C57BL/6J mice were studied. To suppress endogenous AVP, mice were placed on a high-water gel diet 1 wk before a 10-μg intraperitoneal injection of desmopressin (dDAVP) at ZT5 or ZT17, and then samples were collected 1 h later. dDAVP administered during the active period resulted in a more diluted plasma, reflected by lower plasma osmolality at ZT18. This response is associated with increased abundance of AQP2 phosphorylated at S256 and S261 in the outer medulla of the ZT18 mice compared with the ZT6 mice. Thus, dDAVP is more effective during the active period when water intake is greatest, and there is enhanced renal filtration and reabsorptive capacity. Conversely, when the V2R was inhibited with tolvaptan, urine flow peaked 2 h postinjection in the male and female mice, regardless of whether it was ZT18 or ZT6. However, male mice produced significantly more urine than the female mice in response to the tolvaptan. In conclusion, both time of day and sex significantly influenced renal responses to V2R-targeted therapies. Desmopressin (dDAVP) is more potent during the active phase in mice, resulting in a greater plasma dilution and a potential risk for hyponatremia. This time-of-day difference likely reflects increased water intake during the active period, as well as diurnal changes in renal physiology, including higher glomerular filtration, a stronger medullary interstitial osmotic gradient, and increased AQP2 phosphorylation at S256 that together promote greater water retention.
Transcription factor 21 deletion from podocyte precursors as a model for congenital nephrotic syndrome.
Dalal V, Zhou Y, Deb DK … +9 more , Thomson BR, Nelson JW, Ledogar G, Misener S, Maekawa H, Chang A, Chung E, Park JS, Quaggin SE
Am J Physiol Renal Physiol · 2026 Jun · PMID 42090190 · Publisher ↗
Nephrotic syndrome is one of the most common causes of kidney disease in children. The glomerular and tubulointerstitial changes that occur in the kidney due to this state of high-grade proteinuria are incompletely under...
Nephrotic syndrome is one of the most common causes of kidney disease in children. The glomerular and tubulointerstitial changes that occur in the kidney due to this state of high-grade proteinuria are incompletely understood. Here, we report a mouse model of congenital nephrotic syndrome, induced by deletion of transcription factor 21 () from podocyte precursors, that can be used to study the injury sustained by young kidneys in response to nephrotic range proteinuria. is required for normal podocyte development. Our laboratory previously showed that deletion of from early podocyte progenitors abrogated the formation of normal foot processes in embryonic mice. We now show the postnatal phenotype of this deletion characterized by progressive nephrotic range proteinuria as early as two weeks of age. These mice developed worsening glomerulosclerosis and tubulointerstitial fibrosis, resulting in early mortality. Single-cell RNA sequencing of kidneys from these mice demonstrated structural and developmental defects in podocytes caused by the absence of . Parietal epithelial cells in mutant kidneys underwent secondary changes that have been shown to promote glomerular injury in other models of kidney disease. In addition, we observed tubulointerstitial changes coincident with the massive proteinuria produced by this genetic model-namely, an expansion of fibroblasts accompanied by the appearance of a new injury cell state in the loop of Henle. These changes preceded the onset of severe, irreversible injury, presenting pathways that could be intervened upon early in the disease to prevent progression of renal fibrosis. This study generated a comprehensive kidney-wide single-cell transcriptomic dataset of a murine model of childhood nephrotic syndrome developed by the deletion of transcription factor 21 () from early podocyte precursors. Our transcriptomic data provide further mechanistic insights into how TCF21 regulates podocyte health and development while enabling interrogation of how the tubulointerstitium responds to massive proteinuria.
Loss of proximal tubule lactate dehydrogenase A exacerbates nephrotoxic acute kidney injury through metabolic dysregulation.
Lu Y, Zmijewska AA, Zhang Y … +9 more , Osis G, Cheung MD, Wilson L, Jiang Y, Vejendla S, Traylor A, Barnes S, George JF, Agarwal A
Am J Physiol Renal Physiol · 2026 Jun · PMID 42089792 · Full text
Acute kidney injury (AKI) involves abrupt loss of kidney function driven in part by proximal tubule metabolic stress, yet the role of glycolytic regulation in tubular injury susceptibility remains unclear. Lactate dehydr...
Acute kidney injury (AKI) involves abrupt loss of kidney function driven in part by proximal tubule metabolic stress, yet the role of glycolytic regulation in tubular injury susceptibility remains unclear. Lactate dehydrogenase A (LDHA) is a key regulator of glycolytic flux and redox balance, but its function in proximal tubules during AKI is poorly defined. In this work, we use a cisplatin-induced AKI model to investigate the role of proximal tubule LDHA in regulating metabolic responses and injury severity. Proximal tubule-specific LDHA knockout mice (PEPCKLDHA) and LDHA controls were subjected to cisplatin-induced AKI. Untargeted metabolomics of kidney cortex and single-nucleus RNA sequencing (snRNA-seq) were performed to define metabolic and cell-specific transcriptional responses. Loss of proximal tubular LDHA exacerbated cisplatin-induced AKI, as evidenced by worsened kidney function and tubular injury, accompanied by increased expression of inflammatory markers following injury. The analysis also showed a distinct metabolic profile at baseline in LDHA-deficient kidneys, which became more pronounced after cisplatin exposure, with coordinated changes in purine and nucleotide metabolism, energy-related metabolites, and pathways linked to redox balance and mitochondrial function. snRNA-seq revealed intrinsic transcriptional changes within proximal tubule cells at baseline and after injury, reflecting cellular stress and metabolic remodeling without strong activation of classic inflammatory gene programs. Together, these findings identify proximal tubular LDHA as a key regulator of metabolic flexibility and injury tolerance in cisplatin-induced AKI, and suggest that disrupted coordination of glycolytic and nucleotide metabolism increases tubular vulnerability, highlighting metabolic regulation as a potential therapeutic target. This study identifies proximal tubule lactate dehydrogenase A (LDHA) as a critical regulator of metabolic flexibility during cisplatin-induced acute kidney injury (AKI). Using a tissue-specific genetic approach and integrated multi-omics, we show that loss of LDHA worsens kidney injury and inflammatory responses while disrupting metabolic adaptation in proximal tubules. These findings highlight metabolic regulation within proximal tubules as a key determinant of injury tolerance and a potential therapeutic target in AKI.
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Am J Physiol Renal Physiol · 2026 May · PMID 42084237 · Publisher ↗
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Depletion of renal cortical collecting duct-secreted PCSK9 in early proteinuria prevents sustained nephrotic syndrome-related hypercholesterolemia.
Molina-Jijon E, Zavala-Guevara IP, Gambut S … +4 more , Gomez-Sierra T, Avila-Casado C, Macé C, Clement LC
Am J Physiol Renal Physiol · 2026 Jun · PMID 42060376 · Publisher ↗
The proprotein convertase subtilisin/kexin 9 (PCSK9) protein is well known for its role in the regulation of plasma cholesterol levels. We previously showed that the initiation of hypercholesterolemia in nephrotic syndro...
The proprotein convertase subtilisin/kexin 9 (PCSK9) protein is well known for its role in the regulation of plasma cholesterol levels. We previously showed that the initiation of hypercholesterolemia in nephrotic syndrome is related to PCSK9 secreted by the cortical collecting duct (CCD), whereas the established phase is due to PCSK9 secreted by the liver. In this study, we investigated whether early neutralization of circulating CCD-secreted PCSK9 could prevent sustained hypercholesterolemia. We showed that PAN rats, a widely used animal model that mimics nephrotic syndrome phenotype of human minimal change disease (MCD), developed increased levels of PCSK9 of CCD origin before peak proteinuria. CCD-secreted PCSK9 followed an increase in the transcription factor sterol regulatory element-binding protein 2 (SREBP2) expression, whereas both SREBP2 and PCSK9 were unmodified and reduced, respectively, in the liver. Treatment of PAN rats with anti-PCSK9 antibodies administrated at or shortly after the onset of proteinuria prevented the development of significant and sustained hypercholesterolemia through the course of PAN. These data confirm that PCSK9 secreted from the kidney initiates the development of hypercholesterolemia in MCD and suggest that early depletion of PCSK9 during the initial stages of MCD prevents sustained hypercholesterolemia. The goal of this study was to investigate the biology of CCD-secreted PCSK9 and its role in MCD-associated hypercholesterolemia. PCSK9 expression was increased in the kidney, but reduced in the liver, suggesting that elevated circulating PCSK9 levels may originate from the kidney. Administration of anti-PCSK9 antibodies targeting circulating kidney-derived PCSK9 prevented the development of significant and sustained hypercholesterolemia in the PAN rat model of human MCD-associated nephrotic syndrome.
Dapagliflozin ameliorates high-fat diet-induced, megalin-mediated autolysosomal dysfunction in proximal tubules via suppression of megalin-dependent endocytosis.
Takemoto K, Hosojima M, Kabasawa H … +10 more , Komochi K, Aoki H, Sugita N, Goto S, Kaseda R, Nagatoishi S, Tsumoto K, Narita I, Yamamoto S, Saito A
Am J Physiol Renal Physiol · 2026 Jun · PMID 42053449 · Publisher ↗
Megalin, a multiligand endocytic receptor in proximal tubules (PTs), mediates the uptake of glomerular-filtered lipotoxic proteins, contributing to tubuloglomerular injury in high-fat diet (HFD)-fed mice. This process is...
Megalin, a multiligand endocytic receptor in proximal tubules (PTs), mediates the uptake of glomerular-filtered lipotoxic proteins, contributing to tubuloglomerular injury in high-fat diet (HFD)-fed mice. This process is characterized by pathologic vacuolation in PTs, which arises due to megalin-dependent autolysosomal dysfunction. Vacuolation is observed exclusively in segment 2 of PTs, which is vulnerable to metabolic stress because of its less robust endolysosomal system. Although receptor-mediated endocytosis (RME) predominates in segment 1, fluid-phase endocytosis (FPE) is more active in segment 2. This study investigates the effects of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, on HFD-induced autolysosomal dysfunction in PTs. In male kidney-specific conditional megalin-knockout mice, both RME and FPE in PTs were diminished compared with controls, as demonstrated by reduced uptake of fluorescent lysozyme and dextran, respectively. Similarly, in male C57BL/6J mice, 5-day dapagliflozin treatment suppressed uptake of both tracers in PTs compared with vehicle treatment, without affecting the glomerular filtration rate. Nine-week-old male C57BL/6J mice were fed an HFD and treated with dapagliflozin or vehicle for 28 days. Dapagliflozin significantly reduced cortical tubule vacuolation and urinary C-megalin excretion, another marker of autolysosomal metabolic overload and dysfunction in PTs. Urinary excretion of the megalin ligand α-microglobulin increased following dapagliflozin treatment via the suppression of megalin's endocytic function. However, renal megalin expression levels remained unchanged, as confirmed by immunoblotting, quantitative PCR, and immunohistochemistry. In conclusion, dapagliflozin alleviates HFD-induced, megalin-mediated autolysosomal dysfunction-particularly in segment 2 of PTs-likely by suppressing megalin-dependent RME and, more notably, FPE. Here, megalin was found to mediate both receptor-mediated and fluid-phase endocytosis in vivo. Dapagliflozin ameliorates high-fat diet-induced autolysosomal dysfunction-particularly in segment 2 of proximal tubules-likely by suppressing megalin-dependent endocytosis without altering megalin expression levels. This suppression reduces metabolic overload in proximal tubules, supporting a renoprotective role for dapagliflozin in chronic kidney disease. These findings highlight a novel mechanism by which dapagliflozin might protect against tubular injury in the context of metabolic stress.
Endogenous oxalate synthesis in mouse models of metabolic dysfunction-associated steatotic liver disease.
Li X, Cunneely OP, Foote JB … +5 more , Burns ZR, Fargue S, Assimos DG, Knight J, Wood KD
Am J Physiol Renal Physiol · 2026 Jun · PMID 42021709 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) may lead to increased urinary oxalate excretion, a risk factor for calcium oxalate kidney stone formation, and progression of chronic kidney disease. We us...
Metabolic dysfunction-associated steatotic liver disease (MASLD) may lead to increased urinary oxalate excretion, a risk factor for calcium oxalate kidney stone formation, and progression of chronic kidney disease. We used mouse models of diet-induced obesity to examine the impact of MASLD on endogenous oxalate synthesis and urinary oxalate excretion. Mice were either fed a high-fat diet to induce mild MASLD, or a high-fat, sucrose, and cholesterol diet (Western diet) to produce metabolic dysfunction-associated steatohepatitis (MASH), a more severe form of MASLD. Liver tissue was collected to measure activities of liver enzymes involved in endogenous oxalate synthesis and oxalate content. Blood and urine were obtained to measure serum creatinine and urinary oxalate excretion. Urinary oxalate excretion was also assessed after administration of hydroxyproline, a known endogenous oxalate precursor. High-fat feeding led to an increase in liver enzymes involved in glyoxylate detoxification and a significant, but modest (∼20%) increase in urinary oxalate excretion compared with control animals. In contrast, Western diet feeding led to a decrease in these enzyme activities and a 47% increase in urinary oxalate excretion compared with controls. Challenging mice with hydroxyproline resulted in significantly higher urinary oxalate excretion in Western diet-fed mice, but not high-fat-fed mice. Mild MASLD modestly increases endogenous oxalate synthesis, whereas MASH results in a profound increase in endogenous oxalate synthesis attributed to significant decreases in activity of hepatic enzymes involved in glyoxylate detoxification. Metabolic dysfunction-associated steatotic liver disease (MASLD) has been reported to lead to increased oxalate synthesis in mouse models. We show here that changes in oxalate synthesis, mediated by complex changes in enzymes involved in glyoxylate metabolism, are dependent on the degree of severity of MASLD, resulting in limited increases in urinary oxalate in mild MASLD, but marked increases in steatohepatitis.
Measuring nephron number in the healthy and diabetic rat kidney in vivo using MRI without contrast agents.
Baldelomar EJ, Charlton JR, Keilhoz S … +5 more , Kohn B, Wilson LD, Xiong LI, Garfinkel A, Bennett KM
Am J Physiol Renal Physiol · 2026 Jun · PMID 41995842 · Full text
We investigated whether physiological oscillations detected by noncontrast resting-state magnetic resonance imaging (rsMRI) can be used to measure functional nephron number, nephron density, or estimated single-nephron g...
We investigated whether physiological oscillations detected by noncontrast resting-state magnetic resonance imaging (rsMRI) can be used to measure functional nephron number, nephron density, or estimated single-nephron glomerular filtration rate (eSNGFR) in vivo. We further investigated whether the observed oscillations below 0.05 Hz reflect tubuloglomerular feedback (TGF). First, we compared features of spectral power of oscillations in rsMRI with total nephron number, nephron density, glomerular filtration rate (GFR), and eSNGFR in healthy Sprague-Dawley rats ( = 20). We then compared features of spectral power to total nephron number in Zucker Diabetic Sprague-Dawley (ZDSD) rats ( = 8) with type-2 diabetes. Finally, we tested the hypothesis that spectral features associated with nephron number reflect TGF by comparing spectra before and after furosemide infusion, which blocks the Na-K-2Cl cotransporter required for TGF and attenuates TGF oscillations. In healthy rats, the median power of rsMRI oscillations below 0.05 Hz in the kidney cortex was significantly correlated ( < 0.05) with nephron number in all animals ( = 0.68) and within sex groups (, males = 0.71; , females = 0.73). Median power in this range was inversely correlated with eSNGFR ( < 0.05, = 0.39). No spectral features were correlated with nephron density or GFR. In ZDSD rats with confirmed pathology, total power between 0.015 and 0.045 Hz was significantly correlated with nephron number ( = 0.59, < 0.05). In both male and female rats, furosemide caused a significant attenuation of power in rsMRI spectral peaks below 0.05 Hz throughout the cortex ( < 0.05). This work demonstrates the noninvasive, in vivo measurement of nephron number in healthy and diabetic rats using rsMRI, and the potential application of rsMRI to detect TGF-associated physiological fluctuations. We previously showed that resting-state magnetic resonance imaging (rsMRI) detects spontaneous physiological oscillations in rat and human kidneys, potentially reflecting autoregulation mechanisms. Here, we apply rsMRI and show that the features of these oscillations can be used to measure nephron number in healthy and diabetic rats, and are associated with the tubuloglomerular feedback mechanism. Because the rsMRI scan is short (∼10 min) and noninvasive, it might be rapidly translated to measure nephron number and function in the clinic.
ENaC processing in rat kidney: effects of salt loading and ADH.
Frindt G, Rohan T, Schreiner R … +1 more , Palmer LG
Am J Physiol Renal Physiol · 2026 Jun · PMID 41995738 · Publisher ↗
We studied the control of processing of the epithelial Na channel (ENaC) through acute dietary Na loading and antidiuretic hormone. Acute salt repletion of Na-depleted rats decreased the abundance of fully processed ENaC...
We studied the control of processing of the epithelial Na channel (ENaC) through acute dietary Na loading and antidiuretic hormone. Acute salt repletion of Na-depleted rats decreased the abundance of fully processed ENaC proteins, assessed as the cleaved forms of α and γENaC and the mature glycosylated form of βENaC, within 2.5 h, despite sustained high levels of aldosterone in plasma. This phenomenon could not be explained by decreased aldosterone, increased Na delivery to the distal nephron, intracellular Na loading of ENaC-expressing cells, or decreased responsiveness of these cells to aldosterone. We found no evidence for the involvement of angiotensin II, atrial natriuretic peptide, or endothelin in the process. Administration of dDAVP to activate V2-type ADH receptors increased the abundance of cleaved γENaC and αENaC within 2 h. Unlike effects of aldosterone, dDAVP also increased the amount of full-length γENaC. Levels of mRNA for ENaC subunits were not raised under these conditions. We conclude that processing of ENaC subunits is modified acutely by aldosterone-independent processes, with Na loading inhibiting the rate of forward trafficking of assembled proteins and ADH stimulating subunit synthesis. We show that two conditions, acute salt loading and antidiuretic hormone administration, can alter ENaC processing and renal salt handling independent of the mineralocorticoid status.
Plasma metabolomics analysis in murine prerenal azotemia reveals changes in energy substrates, amino acid metabolism, and uremic toxins.
Budnick I, Argabright A, Anderson CC … +7 more , Bevers S, Okamura K, He Z, Reisz JA, Baker PR, Montford J, Faubel S
Am J Physiol Renal Physiol · 2026 Jun · PMID 41989826 · Full text
Prerenal azotemia (PRA) accounts for 10%-30% of hospitalized cases of acute kidney injury (AKI). In contrast to AKI from acute tubular injury (ATI), PRA is considered a benign condition, despite evidence that it is assoc...
Prerenal azotemia (PRA) accounts for 10%-30% of hospitalized cases of acute kidney injury (AKI). In contrast to AKI from acute tubular injury (ATI), PRA is considered a benign condition, despite evidence that it is associated with adverse clinical consequences. In this study, we used untargeted metabolomics to study the potential systemic consequences of PRA as compared with ATI. We hypothesized that the PRA and ATI plasma metabolomes would share certain features, since both are marked by a decline in glomerular filtration rate (GFR), but that a unique PRA signature would be identified. Wild-type male C57BL/6 mice were used in established models of ischemic acute kidney injury (iAKI) or PRA induced by intraperitoneal furosemide followed by GFR restoration with normal saline resuscitation. Plasma from iAKI and PRA cohorts were analyzed by mass spectrometry metabolomics. The PRA plasma metabolome was defined by 40 significantly changed metabolites, including 7 uremic toxins, with significant enrichment of tryptophan and fatty acid oxidation metabolites. When comparing models, the PRA and iAKI metabolomes overlap at the individual metabolite level (50% of the PRA metabolome represented in the iAKI metabolome) and share three significantly enriched pathways involved in energy substrate and amino acid metabolism. Further analysis identified cystathionine, kynurenine, and indolepyruvate as possible PRA plasma biomarkers. Our results demonstrate that PRA causes systemic metabolic changes, some of which mirror changes found in ATI. Our results challenge the notion that PRA is inconsequential, and the metabolic pathways and uremic toxins identified herein warrant further study. We completed the first untargeted plasma metabolomics analysis in a murine model of prerenal azotemia (PRA) and demonstrate that PRA has systemic consequences with numerous significantly altered metabolites and pathways. By comparing the metabolite signature to that of acute tubular injury (ATI), novel insights into the potential adverse consequences of PRA and potential methods to distinguish PRA from ATI were identified.
HIF-mediated regulation of glutathione-specific γ-glutamyl cyclotransferase 1 contributes to tubular cell death in renal ischemia-reperfusion injury.
Kihira Y, Homma T, Matsunaga S … +7 more , Yamaguchi K, Tsounapi P, Yamaguchi T, Fujimura Y, Sato E, Tamaki T, Tomita S
Am J Physiol Renal Physiol · 2026 Jun · PMID 41984183 · Publisher ↗
Renal ischemia-reperfusion (I/R) remains a leading cause of acute renal failure in both native and transplanted kidneys. Hypoxia-inducible factor (HIF)-1α is a protective factor against renal I/R injury (rIRI). However,...
Renal ischemia-reperfusion (I/R) remains a leading cause of acute renal failure in both native and transplanted kidneys. Hypoxia-inducible factor (HIF)-1α is a protective factor against renal I/R injury (rIRI). However, the downstream mechanisms through which HIF-1α exerts its protective effects in rIRI remain to be fully elucidated. rIRI was induced in heterozygous HIF-1α knockout (hKO) mice. To establish an in vitro model of rIRI, a human tubular cell line (HK2) was subjected to hypoxia-reoxygenation (H/R). rIRI-induced hKO mice exhibited elevated serum creatinine levels compared with rIRI-induced wild-type (WT) mice. Furthermore, tubular cell death was observed earlier in WT mice during the initial phase of I/R, whereas it was reduced in hKO mice. Phagocytosis of damaged tubular cells by macrophages was diminished in hKO mice, suggesting that the clearance of cellular debris plays a critical role in renal tissue repair and regeneration. Furthermore, glutathione-specific γ-glutamyl cyclotransferase 1 (CHAC1), a known cell death inducer, was upregulated in the tubular cells of WT mice but not hKO mice following I/R. The overexpression of CHAC1 in HK2 cells induced cell death, whereas siRNA-mediated CHAC1 knockdown attenuated cell death in HK2 cells subjected to H/R. These findings collectively suggest that CHAC1 plays a pivotal role in regulating tubular cell death during rIRI. Our findings indicate that controlled cell death induction is essential for rIRI recovery. CHAC1, a key factor in this process, is a potential therapeutic target for rIRI. Here, we reported that HIF-1α upregulates glutathione-specific γ-glutamyl cyclotransferase 1 (CHAC1), a regulator of cell death and oxidative stress, in rIRI. Our results suggested that CHAC1 plays a pivotal role in regulating tubular cell death during rIRI, and the controlled tubular cell death induced by CHAC1 is essential for rIRI recovery. This proposes novel mechanisms underlying rIRI recovery.
The urine metabolomic signature of distal diuretics and diuretic-induced hyponatremia in patients with chronic kidney disease.
Rudolphi CF, Musterd-Bhaggoe U, Ruijter GJG … +2 more , Hoorn EJ, Imenez Silva PH
Am J Physiol Renal Physiol · 2026 May · PMID 41962959 · Publisher ↗
Recent clinical trials have shown that distal nephron-acting diuretics are effective in managing fluid retention and salt-sensitive hypertension in people with chronic kidney disease (CKD). However, their use may be comp...
Recent clinical trials have shown that distal nephron-acting diuretics are effective in managing fluid retention and salt-sensitive hypertension in people with chronic kidney disease (CKD). However, their use may be complicated by diuretic-induced hyponatremia. This study aimed to characterize the metabolomic effects of distal diuretics in people with CKD, including those who develop hyponatremia. Therefore, we analyzed plasma and 24-h urine samples from a previously completed randomized controlled trial including individuals with CKD (mean estimated glomerular filtration rate = 39 ± 13 mL/min/1.73 m) treated with amiloride/hydrochlorothiazide (5 mg/50 mg daily) for 2 wk. The study included 26 participants in whom we analyzed a set of targeted metabolites. Global untargeted metabolomics was performed in a subcohort of 12 participants, including four patients who developed hyponatremia (plasma sodium <136 mmol/L) and eight diuretic-treated controls with stable sodium levels. Distal diuretic therapy decreased plasma glutamine levels and the excretion of several tricarboxylic acid cycle-related metabolites. Furthermore, distal diuretics significantly increased urinary ammonium excretion in the absence of hypokalemia or metabolic acidosis. Untargeted metabolomic analysis revealed 988 unique metabolites in the urine. Among those with hyponatremia, we observed a metabolomic signature of oxidative stress, likely due to altered glutamine and carnitine metabolism. These findings suggest that distal diuretics not only act locally in the distal convoluted tubule but also influence proximal tubular metabolism. In conclusion, our results highlight that distal diuretics induce significant metabolic changes in CKD, with urine metabolomics offering valuable insights into the physiological pathways and mechanisms underlying both therapeutic effects and adverse responses. We assessed the urinary metabolomic fingerprint of treatment with amiloride and hydrochlorothiazide in individuals with CKD stages G3-G4. We identified enhanced ammoniagenesis in the absence of hypokalemia or metabolic acidosis. Patients who developed diuretic-induced hyponatremia exhibited a urinary metabolomic signature of oxidative stress. Our study highlights the interplay between "electrolyte and fluid balance" and "metabolic adaptations" in individuals with CKD who are treated with distal diuretics.
Peak oxygen consumption is positively associated with estimates of oxygen extraction and microvascular blood volume in veterans with chronic kidney disease.
Gollie JM, Kokkinos PF, Patel SS … +6 more , Libin AV, Holley AB, Shara NM, Hazel CG, Kim DJ, Blackman MR
Am J Physiol Renal Physiol · 2026 May · PMID 41962951 · Full text
Peak oxygen consumption (V̇o) is reduced in patients with chronic kidney disease (CKD). Although cardiovascular and skeletal muscle factors are implicated in the declines of V̇o, few studies have evaluated muscle oxygena...
Peak oxygen consumption (V̇o) is reduced in patients with chronic kidney disease (CKD). Although cardiovascular and skeletal muscle factors are implicated in the declines of V̇o, few studies have evaluated muscle oxygenation responses during exercise. We hypothesized that lower V̇o in CKD would be associated with attenuated responses in muscle oxygenation compared with those without CKD. Forty-six male Veterans [CKD stages 3 and 4, = 23; referent controls (REF), = 23] completed the study. Cardiopulmonary exercise testing was performed on a treadmill using the modified Bruce protocol. Peak change in dominant medial gastrocnemius deoxygenated hemoglobin/myoglobin {Δ[deoxy(Hb-Mb)]}, total hemoglobin/myoglobin {Δ[total(Hb-Mb)]}, tissue saturation index (ΔTSI), and ΔTSI reoxygenation half-time recovery (ΔTSI) were assessed via near-infrared spectroscopy (NIRS). V̇o, exercise time, HR, V̇o at gas-exchange threshold (GET), and exercise time after GET were lower in the CKD group versus the REF group ( = 0.002, < 0.001, = 0.020, = 0.044, and = 0.005, respectively). For NIRS outcomes, Δ[total(Hb-Mb)] was lower, and ΔTSI prolonged, in the CKD group compared with the REF group ( = 0.032 and = 0.031, respectively). V̇o was positively associated with HR (CKD, = 0.57, = 0.005; REF, = 0.63, = 0.001) and Δ[total(Hb-Mb)] (CKD, = 0.63, = 0.001; REF, = 0.52, = 0.012) in both groups. Conversely, V̇o was positively associated with Δ[deoxy(Hb-Mb)] in the CKD group only ( = 0.64, < 0.001). These findings suggest that skeletal muscle impairments, in addition to cardiovascular impairments, contribute to reduced V̇o in patients with CKD. Peak oxygen consumption is associated with peak heart rate, oxygen extraction, and microvascular blood volume in patients with chronic kidney disease (CKD), highlighting the importance of cardiovascular and skeletal muscle health in this patient population. Future studies are necessary to determine which exercise approaches are most efficacious at enhancing cardiorespiratory fitness and whether, and to what extent, improvements in cardiorespiratory fitness result from changes in cardiovascular factors, skeletal muscle factors, or a combination of both.
How does the kidney conserve Na in a salt-scarce environment?
Palmer LG, Weinstein AM, Frindt G
Am J Physiol Renal Physiol · 2026 May · PMID 41955132 · Publisher ↗
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GPR183 contributes to renal macrophage infiltration and fibrosis in kidney injury.
Zhang Q, Wang Y, Fan Y … +4 more , Han SS, Xie H, Rhee EP, Wen D
Am J Physiol Renal Physiol · 2026 May · PMID 41954905 · Full text
Macrophages play a key role in kidney inflammation and fibrosis. The oxysterol receptor G protein-coupled receptor 183 (GPR183) is an important immunomodulatory receptor, but its role in kidney disease is undefined. In t...
Macrophages play a key role in kidney inflammation and fibrosis. The oxysterol receptor G protein-coupled receptor 183 (GPR183) is an important immunomodulatory receptor, but its role in kidney disease is undefined. In this study, we investigated the contribution of GPR183 to renal injury using adenine diet-induced chronic kidney disease and folic acid-induced nephropathy models. Both models exhibited marked upregulation of the cholesterol hydroxylases CH25H and CYP7B1, along with increased GPR183 expression in the kidney. Immunofluorescence analysis demonstrated that GPR183 colocalized with M1 macrophage markers within injured kidneys. Genetic deletion of GPR183 selectively reduced renal M1 macrophage accumulation and proinflammatory cytokine expression without affecting M2 macrophage infiltration, leading to improved renal function. GPR183 deficiency also significantly attenuated renal fibrosis, as evidenced by decreased collagen deposition and reduced expression of fibronectin and α-smooth muscle actin. In primary bone marrow-derived macrophages, GPR183 deletion suppressed lipopolysaccharide (LPS) and interferon γ (IFN-γ)-induced M1 polarization through inhibition of NF-κB signaling. Finally, analysis of publicly available human single-cell RNA sequencing data demonstrated substantial GPR183 expression in immune cells, including macrophages, in patients with chronic kidney disease. These findings identify GPR183 as a key regulator of macrophage phenotype in kidney injury and demonstrate that activation of the oxysterol-GPR183 axis promotes inflammatory and fibrotic renal remodeling. Targeting GPR183 may therefore represent a novel therapeutic strategy for the treatment of progressive kidney disease. This study identifies GPR183 as a previously unrecognized regulator of macrophage polarization and renal fibrogenesis. We demonstrate that kidney injury activates an oxysterol-GPR183 signaling axis that promotes NF-κB-dependent M1 macrophage polarization. Genetic deletion of GPR183 selectively limits inflammatory macrophage accumulation, attenuates fibrosis, and preserves renal function, establishing GPR183 as a novel therapeutic target in progressive kidney disease.
NBL1 associates with renal phenotypes in mice, but partial Nbl1 reduction does not ameliorate kidney disease.
Willey CN, Bufi R, Takemon Y … +6 more , Brackett A, Warren A, Spellacy S, Gatti DM, Sheehan S, Korstanje R
Am J Physiol Renal Physiol · 2026 May · PMID 41910154 · Publisher ↗
Increased concentrations of neuroblastoma suppressor of tumorigenicity 1 (NBL1) in the blood have been associated with disease progression in diabetic kidney disease (DKD) and IgA nephropathy. However, it is unclear whet...
Increased concentrations of neuroblastoma suppressor of tumorigenicity 1 (NBL1) in the blood have been associated with disease progression in diabetic kidney disease (DKD) and IgA nephropathy. However, it is unclear whether NBL1 is a causal factor for kidney disease and what is driving these increased concentrations in the blood. To test this, we evaluated heterozygous knockout () mice in two models of kidney injury, X-linked Alport syndrome (XLAS) and chronic low-dose cisplatin treatment, and compared them with wild-type (WT) controls. In parallel, we assessed serum NBL1, kidney function, and damage, and performed a genetic analysis for the drivers of NBL1 concentrations in two independent cohorts of genetically diverse Diversity Outbred mice with XLAS (DO-XLAS), analyzing each cohort separately. Serum NBL1 was consistently associated with reduced glomerular filtration rate (GFR) across both DO-XLAS cohorts, whereas correlations with albumin-to-creatinine ratio (ACR) were variable between cohorts, and not consistently replicated. In both XLAS and cisplatin models, partial reduction of NBL1 (∼50%) in mice did not alter GFR, ACR, or histological injury relative to WT controls. Genetic analysis of NBL1 concentrations in our DO-XLAS cohorts identified associations with loci on Chromosomes 4 and 17. Together, these findings indicate that elevated serum NBL1 reflects kidney injury and, under partial reduction, does not alter disease severity, consistent with NBL1 functioning as a biomarker rather than a causal driver of kidney disease. Elevated NBL1 in blood correlates with end-stage kidney disease in humans with diabetic kidney disease. NBL1 also correlates with renal phenotypes in a cohort of genetically diverse mice with X-linked Alport syndrome. Studies in two different mouse models of kidney disease reveal that elevated NBL1 is not causal to kidney injury, positioning NBL1 as a biomarker with potential applicability across etiologies and clarifying its role as a consequence of renal pathology.
Deletion of Cab39 adaptors results in KS-WNK1 independent accumulation of SPAK in biomolecular condensates.
Ferdaus MZ, Inoue MK, Terker AS … +2 more , Welling PA, Delpire E
Am J Physiol Renal Physiol · 2026 May · PMID 41903110 · Publisher ↗
The sodium-chloride cotransporter (NCC) in the distal convoluted tubule regulates renal sodium reabsorption, potassium homeostasis, and blood pressure. NCC phosphorylation is controlled by extracellular potassium via the...
The sodium-chloride cotransporter (NCC) in the distal convoluted tubule regulates renal sodium reabsorption, potassium homeostasis, and blood pressure. NCC phosphorylation is controlled by extracellular potassium via the with-no-lysine (WNK)-STE20/SPS1-related proline-alanine-rich kinase (SPAK) kinase cascade, proposed to initiate within biomolecular condensates termed WNK bodies. Kidney-specific with-no-lysine kinase (KS-WNK1) and calcium-binding protein 39 (Cab39) play different roles in WNK body formation and dissolution. Although KS-WNK1 is required for organizing WNK bodies, previous studies suggest that Cab39 promotes SPAK translocation from the WNK bodies to the apical membrane; Cab39 deletion traps phosphorylated SPAK in intracellular puncta and suppresses NCC phosphorylation. Whether these puncta represent bona fide WNK bodies or distinct condensates is unknown. To test whether SPAK puncta require KS-WNK1, we generated mice with distal convoluted tubule-specific deletion of both Cab39 isoforms and KS-WNK1 (triple knockout). NCC, phosphorylated SPAK, and WNK4 expression and localization were assessed by immunoblotting, immunofluorescence, and quantitative (PCR) under low- and high-potassium diets that activate or inhibit the WNK-SPAK-NCC pathway. Despite elevated WNK4, triple-knockout mice exhibited marked NCC hypo-phosphorylation. Phosphorylated SPAK accumulated in cytoplasmic puncta resembling WNK bodies even without KS-WNK1, indicating they are distinct from canonical WNK bodies. Under high-potassium conditions, when WNK4 and SPAK are dephosphorylated, these puncta were absent, suggesting dependence on upstream kinase activity. Thus, SPAK puncta form independently of KS-WNK1, previously considered necessary for WNK body formation, revealing distinct signaling condensates. In this study, we identify novel biomolecular condensates (puncta) that appear in the absence of KS-WNK1, a component of WNK bodies. Mice knockout for both KS-WNK1 and Cab39 adaptor proteins exhibit large SPAK-containing puncta that also comprise WNK4 and L-WNK1. These puncta are p62-positive and ubiquitin-negative, indicating that they are sequestrating rather than degrading structures. Formation of these puncta requires active phosphorylation, as they are not observed in mice fed with a high K diet.
Therapeutic effects of imidazoline 2 receptor activation on lower urinary tract dysfunction in a mouse model of spinal cord injury.
Hashimoto M, Karnup S, Daugherty SL … +10 more , Cho KJ, Matsuoka K, Kimura S, Kamijo T, Sugimoto K, Shimizu N, Uemura H, Fujita K, Beckel JM, Yoshimura N
Am J Physiol Renal Physiol · 2026 May · PMID 41902699 · Publisher ↗
This study evaluated the effects of the imidazoline I2 receptor (I2R) agonist 2-(2-benzofuranyl)-2-imidazoline (2BFI) on lower urinary tract dysfunction (LUTD) in a mouse spinal cord injury (SCI) model. Female mice were...
This study evaluated the effects of the imidazoline I2 receptor (I2R) agonist 2-(2-benzofuranyl)-2-imidazoline (2BFI) on lower urinary tract dysfunction (LUTD) in a mouse spinal cord injury (SCI) model. Female mice were divided into three groups: spinal intact (SI), SCI with vehicle, and SCI with 2BFI beginning 2 wk postinjury. SCI was induced by complete Th8-9 spinal transection. Four weeks after SCI, conscious cystometrograms (CMG) and external urethral sphincter (EUS) electromyography (EMG) were recorded. L6-S1 dorsal root ganglia (DRG) were collected for qPCR analysis of TRPV1, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS). In a separate group of animals, intrathecal (i.t.) 2BFI was tested during CMG/EMG in SCI. Organ bath studies assessed 2BFI-induced relaxation in bladder strips precontracted with KCl or carbachol. SCI mice showed increased nonvoiding contractions (NVCs) and reduced voiding efficiency versus SI. 2BFI significantly decreased NVCs, improved voiding efficiency, and prolonged EUS relaxation, evident as reduced EMG activity compared with vehicle. SCI-induced upregulation of TRPV1, TNF-α, and iNOS in DRG was significantly attenuated by 2BFI. I.t. 2BFI reduced residual urine and NVCs and increased EUS relaxation in SCI mice. In organ baths, 2BFI produced significant relaxation of precontracted bladder strips from both SI and SCI mice. I2R activation in the lumbosacral spinal cord and bladder may provide an effective therapeutic strategy for SCI-induced LUTD. This study shows that selective activation of the imidazoline-2 receptor improves both detrusor overactivity and detrusor-sphincter dyssynergia after spinal cord injury. Systemic and intrathecal administration of 2BFI produced coordinated actions in the spinal cord and lower urinary tract, including enhanced relaxation of the external urethral sphincter, reduced inflammation mediated by C-fiber afferents, and direct relaxation of bladder smooth muscle, indicating a promising therapeutic target.
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