American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Endothelin-1 signaling in the kidney: recent advances and remaining gaps.
Brooks AJ, Gallego-López MDC, De Miguel C
Am J Physiol Renal Physiol · 2025 Jun · PMID 40272184 · Full text
The involvement of endothelin-1 (ET-1) in the maintenance of kidney function as well as its role in renal pathophysiology has been appreciated for decades; however, there still exist important gaps in knowledge in our un...
The involvement of endothelin-1 (ET-1) in the maintenance of kidney function as well as its role in renal pathophysiology has been appreciated for decades; however, there still exist important gaps in knowledge in our understanding of the mechanistic pathways activated by this system in the kidney. The purpose of this article is to review recent advances in the field, as well as to underscore areas that need more investigation, with an emphasis on the interplay of ET-1 with inflammation, sex differences, circadian rhythms of renal function, the most recent clinical trials involving the ET-1 system, and the interaction between microRNAs and the ET-1 system.
Deletion of the prostaglandin EP4 receptor in the kidney tubule of mature mice alters kidney water handling only in males.
Esteva-Font C, Zheng X, Rudolphi CF … +3 more , Hansen TPK, Hoorn EJ, Fenton RA
Am J Physiol Renal Physiol · 2025 Jun · PMID 40261807 · Publisher ↗
Prostaglandin E2 (PGE) is a lipid mediator modulating several aspects of kidney function. PGE acts via four prostanoid receptors, EP1 to EP4. In renal tubules, EP4 has very low expression, yet a role for EP4 in maintaini...
Prostaglandin E2 (PGE) is a lipid mediator modulating several aspects of kidney function. PGE acts via four prostanoid receptors, EP1 to EP4. In renal tubules, EP4 has very low expression, yet a role for EP4 in maintaining water balance has been proposed. The major aim of this study was to clarify the role of the EP4 receptor in the kidney tubule of adult mice for body water homeostasis. To examine this, a mouse model with doxycycline-dependent deletion of EP4 along the renal tubule (Pax8Cre system) was developed and phenotyped with respect to water handling. Two weeks after doxycycline treatment, EP4 mRNA expression (RT-qPCR) was reduced by >80% in the medulla of male and female knockout mice () compared with controls (). With free access to water, there were no detectable differences between genotypes in food intake, body weight, or plasma biochemistries. Male, but not female, mice had a small but significantly higher basal urinary output with decreased osmolality, concomitant with lower urinary Na, K, Cl, urea, and creatinine concentrations. The urea channel UT-A1 was reduced in the medulla, but otherwise no major differences in the levels of proteins involved in water balance were observed between genotypes. There were no differences between genotypes in their ability to concentrate urine during a 14-h water restriction or after treatment with the vasopressin V2 receptor agonist 1-deamino-8-d-arginine-vasopressin. mice of both sexes excreted an acute water load similarly to control mice. In conclusion, EP4 in the renal tubule has a mild role in renal water handling, but only in male mice. This new model provides a novel tool for assessing the role of EP4 in kidney tubule function in various (patho)physiological conditions independently of developmental abnormalities or systemic effects. Acting through the EP1-EP4 receptors, prostaglandin E2 (PGE) modulates various aspects of kidney function. Despite extremely low expression in the collecting duct, EP4 has been proposed to play a key role in regulation of Aquaporin-2 and water balance. In this study, we show that EP4 only plays a mild role in kidney water handling in male mice, calling into question the standard concepts presented in physiology textbooks regarding PGE actions on the collecting duct.
Corrigendum for Bahena-Lope et al., volume 326, 2024, p. F460-F476.
Am J Physiol Renal Physiol · 2025 May · PMID 40260925 · Publisher ↗
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Corrigendum for Chen et al., volume 314, 2018, p. F572-F583.
Am J Physiol Renal Physiol · 2025 May · PMID 40260924 · Publisher ↗
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Renal ischemia alters the mRNA and miRNA profile of vasculature-related genes in scattered tubular-like cells from female pigs.
Kazeminia S, Rajagopalan KS, Zhu XY … +5 more , Tang H, Chade AR, Irazabal MV, Lerman LO, Eirin A
Am J Physiol Renal Physiol · 2025 May · PMID 40241609 · Full text
Scattered tubular-like cells (STCs) are renal tubular cells that survive episodes of renal injury and acquire progenitor-like characteristics to repair other damaged kidney cells. STCs release proangiogenic factors in cu...
Scattered tubular-like cells (STCs) are renal tubular cells that survive episodes of renal injury and acquire progenitor-like characteristics to repair other damaged kidney cells. STCs release proangiogenic factors in culture and induce microvascular proliferation in injured murine kidneys in vivo. Renovascular disease (RVD) compromises the reparative capacity of STCs, but the underlying mechanisms remain unknown. We hypothesized that RVD alters the expression of vasculature-related genes in swine STCs and impair their vasculoprotective properties. CD24/CD133 STCs were harvested from female pig kidneys after 10 wk of RVD or sham ( = 6 each), and the mRNA profiles of vasculature-related genes were analyzed using mRNA and microRNA seq ( = 3/group). STC expression of candidate differentially expressed (DE) genes and their capacity to induce human umbilical endothelial cells (HUVECs) to form tube-like networks were subsequently assessed in vitro before and after micro-RNA (miRNA) modulation ( = 6 each). mRNA-seq identified 67 upregulated and 42 downregulated vasculature-related genes in RVD-STCs. Four miRNAs were upregulated and 12 downregulated in RVD-STCs and found to target 31.3% to 40.5% of DE vasculature-related genes. Modulation in vitro of representative miRNAs decreased RVD-STC expression of anti-angiogenic and increased expression of proangiogenic target genes, respectively. Furthermore, this restored the ability of STCs to induce HUVEC tube formation on Matrigel that was impaired in RVD. Chronic renal ischemia alters the expression of vasculature-related genes in swine STCs, likely through posttranscriptional mechanisms, impairing their proangiogenic activity. These observations may contribute to develop novel approaches to preserve the reparative capacity of STCs in individuals with RVD. The intrinsic reparative capacity of the adult mammalian kidney is restricted to the ability of scattered tubular-like cells (STCs) to repair damaged kidney cells. Our study provides evidence that chronic renal ischemia alters the mRNA/miRNA profile of angiogenic/vascular development genes of swine STCs, limiting their potential to repair injured tubular cells. Our observations may assist in developing new therapies to improve renal repair in individuals with chronic renal ischemia.
Proximal tubule pannexin 1 contributes to mitochondrial dysfunction and cell death during acute kidney injury.
Poudel N, Zheng S, Skrypnyk N … +12 more , Sung SJ, Goggins E, Nash WT, Pavelec C, Yee M, Balogun I, Medina CB, Yao J, Rosin DL, Leitinger N, Ravichandran KS, Okusa MD
Am J Physiol Renal Physiol · 2025 Jun · PMID 40241514 · Full text
Pannexin 1 (Panx1) is a membrane-associated channel that, when activated, facilitates the release of small metabolites into the extracellular environment. These metabolites signal as damage-associated molecular patterns...
Pannexin 1 (Panx1) is a membrane-associated channel that, when activated, facilitates the release of small metabolites into the extracellular environment. These metabolites signal as damage-associated molecular patterns (DAMP) and initiate inflammation. Upregulation and activation of Panx1 is one of the early events during inflammatory injury. Animal models show that a lack of Panx1 is protective against acute kidney injury (AKI). How Panx1 modulates AKI is poorly understood. We utilized both in vivo and in vitro models of PANX1 overexpression to study mitochondrial function, cell death, and inflammation to evaluate how Panx1 contributes to AKI. We used two models of AKI, ischemia-reperfusion injury (IRI) and cisplatin-induced AKI (cis-AKI), in animals that overexpress PANX1 globally or specifically in the proximal tubule or in the endothelium. Cisplatin-induced injury was investigated in vitro in PANX1-overexpressing proximal tubule cells in culture. Both global and proximal tubule-specific overexpression of PANX1 exacerbated AKI, whereas endothelium-specific overexpression had no effect. Panx1-dependent metabolite release and alterations in the intracellular compartment in proximal tubules independently contributed to cell death in vitro. PANX1 overexpression impaired mitochondrial function and increased mitochondrial reactive oxygen species (ROS) production. PANX1 overexpression resulted in increased inflammation in the kidneys during cis-AKI. We showed that PANX1 overexpression resulted in overt renal injury during AKI that is in part mediated by reduced mitochondrial function, increased cell death, and inflammation. Selective strategies to inhibit Panx1 could help prevent or treat AKI. Despite the huge medical, economical, and quality of life burden that AKI poses to patients, there are no Food and Drug Administration (FDA)-approved therapeutic or pharmaceutical interventions for AKI. Pannexin 1 (Panx1), which is upregulated in patients with AKI as well as in animals that develop experimental AKI, plays a crucial role in mediating both inflammation and cell death during AKI. Our findings suggest clinical interventions with molecules that inhibit Panx1 channel activity could improve outcomes in AKI patients.
Kir4.1/Kir5.1 of distal convoluted tubule is required for short-term angiotensin-II-induced stimulation of Na-Cl cotransporter.
Duan XP, Meng XX, Xiao Y … +4 more , Zhang CB, Gu R, Lin DH, Wang WH
Am J Physiol Renal Physiol · 2025 Jun · PMID 40241495 · Publisher ↗
Angiotensin-II (Ang-II) perfusion stimulates inwardly-rectifying potassium channels 4.1 and 5.1 (Kir4.1/Kir5.1) in distal convoluted tubule (DCT) and thiazide-sensitive Na-Cl cotransporter (NCC). The aim of the present s...
Angiotensin-II (Ang-II) perfusion stimulates inwardly-rectifying potassium channels 4.1 and 5.1 (Kir4.1/Kir5.1) in distal convoluted tubule (DCT) and thiazide-sensitive Na-Cl cotransporter (NCC). The aim of the present study is to explore the role of Kir4.1/Kir5.1 in mediating the effect of Ang-II on NCC. We used immunoblotting and patch-clamp experiments to examine the effect of 1- or 7-day Ang-II perfusion on basolateral Kir4.1/Kir5.1 in the DCT and NCC using kidney-tubule-specific (Ks) angiotensin II type 1a receptor (AT1Ar)-knockout (KO), Ks-Kir4.1-knockout and the corresponding wild-type mice. Ang-II perfusion for 1 and 7 days increased phospho-NCC (pNCC) and total-NCC (tNCC) expression and the effect of Ang-II perfusion on pNCC and tNCC was abolished in Ks-AT1aR-KO. Ang-II perfusion for 1 day robustly stimulates Kir4.1/Kir5.1 in the late DCT (DCT2) and to a lesser degree in the early DCT (DCT1), an effect was absent in Ks-AT1aR-KO mice. However, Ang-II perfusion for 7 days did not further stimulate Kir4.1/Kir5.1 in the DCT2 and only modestly increased Kir4.1/Kir5.1-mediated K currents in DCT1. Deletion of Kir4.1 not only significantly decreased the expression of pNCC and tNCC, but also abolished the effect of 1-day Ang-II perfusion on the expression of phospho-with-no-lysine kinase-4 (pWNK4), phospho-ste-20-proline-alanine-rich kinase (pSPAK), Pncc, and tNCC. However, 7-day Ang-II perfusion was still able to significantly stimulate the expression of pSPAK, pWNK4, pNCC, and tNCC, and increased thiazide-induced natriuresis in Ks-Kir4.1-KO mice without obvious changes in K channel activity in the DCT. We conclude that short-term Ang-II-induced stimulation of pWNK4, pSPAK, and pNCC depends on Kir4.1/Kir5.1 activity. However, long-term Ang-II is able to directly stimulate pWNK4, pSPAK, and pNCC by a Kir4.1/Kir5.1 independent mechanism. We investigated the role of Kir4.1/Kir5.1 in mediating the effect of short-term Ang-II on Na-Cl cotransporter (NCC) expression/activity. We demonstrated that Kir4.1/Kir5.1 in the distal convoluted tubule is required for short-term Ang-II-induced stimulation of with-no-lysine-kinase 4 (WNK4), ste20-proline-alanine-rich kinase (SPAK), and NCC. However, sustained Ang-II stimulation is expected to activate WNK4, SPAK, and NCC by Kir4.1/Kir5.1-independent mechanism.
Lack of a role of NHE4 in renal ammonia metabolism.
Lee HW, Harris AN, Hyndman KA … +1 more , Weiner ID
Am J Physiol Renal Physiol · 2025 Jun · PMID 40235211 · Full text
The cation exchanger, Na/H exchanger isoform 4 (NHE4), has been thought to have a central role in renal ammonia metabolism and handling by acting in a Na for NH exchange mode at the basolateral plasma membrane in the thi...
The cation exchanger, Na/H exchanger isoform 4 (NHE4), has been thought to have a central role in renal ammonia metabolism and handling by acting in a Na for NH exchange mode at the basolateral plasma membrane in the thick ascending limb (TAL) of the loop of Henle. These studies aimed to determine the effect of NHE4 deletion on ammonia metabolism under basal conditions and in response to metabolic acidosis. Constitutive NHE4 deletion resulted in increased urine ammonia excretion associated with significantly lower urine pH; this increase did not lead to metabolic alkalosis. In response to exogenous acid-loading, NHE4 deletion did not impair the changes in ammonia excretion. Immunoblot analysis and immunohistochemistry showed mild increases in proximal tubule ammoniagenic enzyme expression with NHE4 deletion. Both immunoblot analysis and immunohistochemistry showed no detectable NHE4 protein expression in the mouse kidney. Single-nucleus RNAseq of mouse kidneys showed no NHE4 mRNA expression in renal epithelial cells. Analysis of five publicly available mouse and human cell-specific RNAseq datasets also showed a lack of NHE4 mRNA expression in the TAL. We conclude that NHE4 is unnecessary for ammonia metabolism either under basal conditions or in response to acid-loading because it is not expressed in the TAL. NHE4 has previously been suggested to mediate a critical role in renal ammonia metabolism through its role in thick ascending limb (TAL) ammonia transport. This manuscript shows that its deletion does not alter renal ammonia handling and that neither the mouse nor human kidney expresses NHE4 in the TAL.
The knock-out of paracingulin attenuates hypertension through modulation of kidney ion transport.
Rouaud F, Meens MJ, Yvon R … +10 more , Hautefort A, Legouis D, Mean I, Jond L, Maillard M, Kwak BR, Moll S, Seigneux S, Feraille E, Citi S
Am J Physiol Renal Physiol · 2025 Jun · PMID 40204428 · Publisher ↗
Hypertension is a major risk factor for human morbidity and mortality, and the junctional protein paracingulin (CGNL1, JACOP) is required for the development of hypertension in a Dahl salt-sensitive rat model and is link...
Hypertension is a major risk factor for human morbidity and mortality, and the junctional protein paracingulin (CGNL1, JACOP) is required for the development of hypertension in a Dahl salt-sensitive rat model and is linked to human hypertension in genome wide association studies. However, the mechanism through which CGNL1 may regulate hypertension is unknown. Here, we address this question using a mouse model, where hypertension is induced by unilateral nephrectomy and angiotensin II infusion (N+A protocol). Although untreated WT and CGNL1-KO mice showed similar blood pressure, the N+A protocol induced hypertension in WT mice but not in CGNL1-KO mice. We show by immunolocalization and transcriptomic analysis that CGNL1 is expressed throughout the kidney tubules and in the endothelium of blood vessels, but not in smooth muscle. The N+A protocol induced decreased potassium urinary excretion in wild-type (WT), but not in CGNL1-KO mice. Immunoblot analysis shows that the KO of CGNL1 blunted the N+A-induced changes in the expression levels and activation of tubular ion transporters, including the Na/H exchanger 3 (NHE3) and the thiazide-sensitive Na-Cl cotransporter (NCC), and blunted the angiotensin II-dependent changes in the levels and/or activation of AMP-activated protein kinase (AMPK), ERK and myosin light chain. In contrast, myography showed comparable vascular reactivity in thoracic aortas and mesenteric arteries isolated from WT or CGNL1-KO mice. Together, these results suggest the KO of CGNL1 attenuates hypertension by uncoupling angiotensin II signaling in kidney tubule cells, indicating a novel pathway of regulation of signaling by a junctional protein. The knock-out of paracingulin (CGNL1) prevents the development of hypertension in a unilateral nephrectomy/angiotensin II infusion model (N+A) in mice and this antihypertensive effect likely depends on uncoupling of angiotensin II from stimulation of sodium transporter activity in kidney tubules rather than on alteration of resistance blood vessel contractility.
Adequate salt intake is essential for candesartan-treated rats to maintain renal function.
Xie A, Xiao L, Zhang M … +11 more , Duan H, Ren Z, Wang P, Jia Y, Xu J, Chen X, Liu M, Wang W, Xue Y, Lou J, Wang X
Am J Physiol Renal Physiol · 2025 Jun · PMID 40204358 · Publisher ↗
Dietary salt restriction and angiotensin-II receptor-1 blockade (ARB) are commonly recommended for patients with renal and cardiovascular diseases. To explore what salt diet was suitable for the ARB users and what measur...
Dietary salt restriction and angiotensin-II receptor-1 blockade (ARB) are commonly recommended for patients with renal and cardiovascular diseases. To explore what salt diet was suitable for the ARB users and what measurements predicted acute kidney injury (AKI), we evaluated the impact of low (0.02%, LS), normal (0.4%, NS), and high (2%, HS)-salt diets on renal function and urinary exosomal sodium-hydrogen exchanger-3 (NHE3), sodium-potassium-chloride cotransporter-2 (NKCC2), sodium-chloride cotransporter (NCC), and aquaporin-1 (AQP1) in candesartan-treated rats. All rats were given candesartan (1 mg/kg/day, ip) except as indicated. Relative to NS control, increased serum creatinine (SCr) but decreased creatinine clearance (Ccr) was observed in consecutive LS rats for 7 days with morphological kidney abnormalities. Similar changes at were observed in the food-switching rats from NS to LS with elevated urine osmolality and creatinine but decreased sodium concentrations. Urinary exosomal NHE3, NKCC2, NCC, and AQP1 were increased in the consecutive LS rats with elevated serum renin, angiotensin-II, and aldosterone. They were increased at in food-switching rats, 2 days earlier than changes in SCr and Ccr, but similar to urine kidney injury molecule-1. Renal and apical-membranous NHE3 and NKCC2 were increased, but AQP1 was decreased with decreased renal angiotensinogen and angiotensin-II receptor type I (AT1R). A moderate HS reversed the changes seen in food-switching rats in SCr, Ccr, and urinary exosomal measurements and improved the kidney morphological abnormalities. Thus, dietary salt restriction induces a prerenal/reversible kidney injury in candesartan-treated rats; urinary exosomal NHE3, NKCC2, NCC, and AQP1 may serve as early biomarkers for the damage. Dietary salt restriction in candesartan-treated rats increases serum creatinine and urinary KIM-1 but decreases creatinine clearance with renal morphological abnormalities. Urinary exosomal NHE3, NKCC2, NCC, and AQP1 increase 2 days earlier than the changes of serum creatinine and creatinine clearance. Moderate high-salt diet reverses those changes with improved renal morphology. Extreme salt restriction should be avoided during candesartan treatment; urinary exosomal NHE3, NKCC2, NCC, and AQP1 may serve as early predictors of the acute kidney injury.
PLVAP: the new villain in glomerular endothelial cell injury.
Alimperti S, Levi M
Am J Physiol Renal Physiol · 2025 Sep · PMID 40184239 · Publisher ↗
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Prevention of hypertension-induced renal vascular dysfunction through a p66Shc-targeted mechanism.
Miller B, Imig JD, Li M … +4 more , Schupbach P, Woo S, Benbrook DM, Sorokin A
Am J Physiol Renal Physiol · 2025 May · PMID 40172516 · Full text
Renal microvascular injury occurs in most patients with hypertension-induced nephropathy (HN). We have shown that overexpression of adaptor protein p66Shc is implicated in the loss of renal microvascular reactivity in hy...
Renal microvascular injury occurs in most patients with hypertension-induced nephropathy (HN). We have shown that overexpression of adaptor protein p66Shc is implicated in the loss of renal microvascular reactivity in hypertensive rats. Since sulfur heteroarotinoid A2 (SHetA2) modulates p66Shc, we tested whether SHetA2 would restore renal microvascular reactivity and mitigate kidney injury in a rat HN model. Dahl salt sensitive (SS) and p66Shc knockout (p66Shc-KO) rats were used in a well-established rat model of HN, characterized by severe renal vascular dysfunction. SHetA2 was either added acutely to isolated rat afferent arterioles or chronically administrated to rats during HN development. The ability of SHetA2 treatment to restore afferent arteriolar contraction in response to increased perfusion pressure or ATP was evaluated using the perfused juxtamedullary nephron preparation. The progression of renal damage was evaluated by measuring urinary protein excretion and conducting analysis of glomerular injury. Comparison of renal microvascular responses to perfusion pressure in p66Shc-KO rats and parental SS rats, in the presence and absence of acute preincubation with SHetA2, revealed a dose-dependent ability of SHetA2 to restore renal microvascular reactivity in SS rats with little effect upon p66Shc knockouts. Moreover, chronic treatment with SHetA2 prevented loss of renal microvascular responses and decline in renal function. SHetA2 was more potent and effective in males compared with females. Targeting p66Shc with SHetA2 diminishes renal damage and restores renal afferent arteriolar reactivity caused by hypertension. These results justify further translation of these findings to develop SHetA2 for prevention and treatment of hypertension-induced kidney damage. Acute preincubation with modulator of p66Shc signaling sulfur heteroarotinoid A2 (SHetA2) revealed dose-dependent ability of SHetA2 to restore renal microvascular reactivity in rats with hypertension-induced nephropathy. Moreover, chronic treatment with SHetA2 prevented loss of renal microvascular responses and decline in renal function. Thus, targeting p66Shc with SHetA2 diminishes renal damage and restores renal afferent arteriolar reactivity caused by hypertension.
The role of IGFBP-1 in the clinical prognosis and pathophysiology of acute kidney injury.
Holthoff JH, Karakala N, Basnakian AG … +10 more , Edmondson RD, Fite TW, Gokden N, Harville Y, Herzog C, Holthoff KG, Juncos LA, Reynolds KL, Shelton RS, Arthur JM
Am J Physiol Renal Physiol · 2025 May · PMID 40172487 · Full text
The ability to predict progression to severe acute kidney injury (AKI) remains an unmet challenge. Contributing to the inability to predict the course of AKI is a void of understanding of the pathophysiological mechanism...
The ability to predict progression to severe acute kidney injury (AKI) remains an unmet challenge. Contributing to the inability to predict the course of AKI is a void of understanding of the pathophysiological mechanisms of AKI. The identification of novel prognostic biomarkers could both predict patient outcomes and unravel the molecular mechanisms of AKI. We performed a multicenter retrospective observational study from a cohort of patients following cardiac surgery. We identified novel urinary prognostic biomarkers of severe AKI among subjects with early AKI. Of 2,065 proteins identified in the discovery cohort, insulin-like growth factor binding protein 1 (IGFBP-1) was the most promising. We validated IGFBP-1 as a prognostic biomarker of AKI in 213 patients. In addition, we investigated its role in the pathophysiology of AKI using a murine model of cisplatin-induced AKI (CIAKI). Urinary IGFBP-1 concentration in samples collected from patients with stage 1 AKI following cardiothoracic surgery was significantly higher in patients who progressed to severe AKI compared with patients who did not progress beyond stage 1 AKI (40.28 ng/ml vs. 2.8 ng/ml, < 0.0001) and predicted the progression to the composite outcome (area under the curve: 0.85, < 0.0001). IGFBP-1 knockout mice showed less renal injury, cell death, and apoptosis following CIAKI, possibly through increased activation of the insulin growth factor receptor 1. IGFBP-1 is a clinical prognostic biomarker of AKI and a direct mediator of the pathophysiology of AKI. Therapies that target the IGFBP-1 pathways may help alleviate the severity of AKI. The ability to predict progression to severe AKI remains an unmet challenge. Early prognostic biomarkers of AKI hold promise to improve patient outcomes by early implementation of clinical therapy, as well as unravel the pathophysiological mechanisms of AKI. Here, we present a novel urinary biomarker, IGFBP-1, that predicts the progression to severe AKI following cardiac surgery. In addition, we show that IGFBP-1 mice are protected against CIAKI, suggesting a mechanistic role for IGFBP-1 in AKI.
ASK1 limits kidney glucose reabsorption, growth, and mid-late proximal tubule KIM-1 induction when diabetes and Western diet are combined with SGLT2 inhibition.
Crespo-Masip M, Goodluck HA, Kim YC … +7 more , Oe Y, Roach AM, Kanoo S, Lopez N, Zhang H, Badal SS, Vallon V
Am J Physiol Renal Physiol · 2025 May · PMID 40152436 · Full text
Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor (ASK1i) that attenuated the decline in creatinine-based estimated GFR in humans with type 2 diabetes and kidney disease but increased the rate of acute kid...
Selonsertib is an apoptosis signal-regulating kinase 1 inhibitor (ASK1i) that attenuated the decline in creatinine-based estimated GFR in humans with type 2 diabetes and kidney disease but increased the rate of acute kidney injury. This study explored the individual and combined kidney effects of selonsertib and the antihyperglycemic sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in Western diet-fed male Akita mice, a murine model of early type 1 diabetes mellitus showing signs of systemic but no kidney inflammation. ASK1i reduced elevated plasma levels of proinflammatory cytokines/chemokines (IL-6, MCP1/CCL2, KC/CXCL1, and IP-10/CXCL10) without significantly changing hyperglycemia, glomerular hyperfiltration, and albuminuria or affecting the blood glucose and glomerular hyperfiltration-lowering effect of SGLT2i. A potential sign of tubular stress, SGLT2i modestly upregulated kidney cortex transcription of proinflammatory and profibrotic genes and distal tubule injury marker Ngal. Adding ASK1i to SGLT2i lowered the transcription of many of these genes, including Ngal. However, ASK1i enhanced kidney glucose reabsorption independent of SGLT2i, and combined ASK1i + SGLT2i increased kidney weight by 30%. This was associated with and positively correlated with the upregulation of the tubular stress/injury marker KIM-1, primarily in the mid-to-late proximal tubule. Combined ASK1i + SGLT2i increased the tubular injury score but not signs of kidney inflammation or fibrosis beyond a robust increase in kidney mRNA expression of Il6, Ccl2 (Mcp1), and Timp1, associated with increased plasma IL-6 levels. The data support the hypothesis that housekeeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in the mid-to-late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition. Selonsertib is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor that attenuated creatinine-based eGFR decline in humans with type 2 diabetes and kidney disease but increased acute kidney injury rates. Here, we report evidence in a murine model of early type 1 diabetes mellitus that housekeeping functions of ASK1 limit glucose reabsorption and the associated growth and cellular stress induced in the mid-to-late proximal tubule by combining hyperglycemia and Western diet with SGLT2 inhibition.
Prolonged unilateral renal ischemia-reperfusion as a model for acute to chronic kidney injury in female mice.
Stowers K, Rudman-Melnick V, Ma Q … +1 more , Devarajan P
Am J Physiol Renal Physiol · 2025 May · PMID 40132202 · Publisher ↗
Acute kidney injury (AKI) is a significant risk factor for developing chronic kidney disease (CKD). Recent studies have highlighted notable gender differences in the susceptibility and expression of both AKI and CKD. The...
Acute kidney injury (AKI) is a significant risk factor for developing chronic kidney disease (CKD). Recent studies have highlighted notable gender differences in the susceptibility and expression of both AKI and CKD. The mechanisms underlying these differences remain unclear, and there is a lack of reliable models for studying the AKI-CKD transition in females. In this study, we evaluated various ischemia times in the unilateral renal ischemia-reperfusion injury (UIR) model in female mice to establish a model for studying the AKI-CKD transition. UIR was induced in the left kidneys of male and female C57Bl/6 mice. Kidney pathology and key injury markers were examined 28 days post-UIR. Comparable pathological changes were observed in female mice subjected to 50- and 60-min ischemia, similar to those in male mice subjected to 30-min UIR. Protein levels of key injury markers, including Vim-1, Krt8, and Acta2, were significantly increased in female mice subjected to 50- and 60-min UIR, comparable to male mice subjected to 30-min UIR, 28 days postinjury. In addition, an increase in mRNA expression of key kidney injury markers , and , along with a decline in expression, was observed in female mice subjected to 50- and 60-min UIR, similar to male mice subjected to 30-min UIR, at 28 days postinjury. Our findings suggest that the optimal ischemia time for inducing CKD changes in female mice is 50-60 min, compared to much shorter injury times in male mice. Our findings identify a reliable timepoint at which female mice subjected to unilateral ischemia-reperfusion consistently develop CKD changes relative to much shorter duration in male mice. We provide a novel model to study the AKI-CKD transition in female mice.
ACE2 deficiency protects against heme protein-induced acute kidney injury.
Croatt AJ, Singh RD, Grande JP … +5 more , Ackerman AW, Gurley SB, Barry MA, Juncos LA, Nath KA
Am J Physiol Renal Physiol · 2025 May · PMID 40131861 · Full text
Angiotensin-converting enzyme 2 (ACE2) exerts countervailing effects on the renin-angiotensin-aldosterone system (RAAS). ACE2 also engages the spike protein of SARS-CoV-2. ACE2 protein has been shown recently to avidly b...
Angiotensin-converting enzyme 2 (ACE2) exerts countervailing effects on the renin-angiotensin-aldosterone system (RAAS). ACE2 also engages the spike protein of SARS-CoV-2. ACE2 protein has been shown recently to avidly bind heme. We examined the pathobiological relevance of this heme-binding property of ACE2 by using the glycerol-induced model of heme protein-mediated AKI (HP-AKI), which is characterized by increased kidney heme content. We studied the response of ACE2-wildtype (ACE2) and ACE2-deficient (ACE2) mice to HP-AKI and quantitated kidney and cellular content of heme under relevant conditions. ACE2-deficient mice, compared with ACE2-wildtype mice, were significantly protected against HP-AKI as reflected by filtration markers, less histological injury, and less expression of apoptosis and ferroptosis markers. ACE2-deficient mice also evinced lesser kidney heme content and a blunted induction of HO-1. HEK293 ACE2-overexpressing cells, compared with HEK293-native cells, when exposed to heme, retained higher amounts of heme. In HP-AKI, ACE2 expression and activity were reduced, and myoglobin and heme, administered independently, reduced ACE2 expression in the otherwise intact mouse kidney. Finally, with more severe HP-AKI, the protective effect of ACE2 deficiency was attenuated. We conclude that ACE2 deficiency confers protection against HP-AKI. We suggest that this reflects the recently recognized binding of heme to ACE2, such binding serving to facilitate renal entry of heme, a known nephrotoxin. These findings uncover a novel pathway of heme-dependent acute kidney injury. This is the first demonstration of the biological relevance of chemical binding of heme by ACE2. Finally, we identify heme proteins and heme as novel determinants of ACE2 expression. ACE2 protein binds heme, which we reasoned would promote heme entry into the kidney and, accordingly, heme protein-mediated acute kidney injury. Our findings support this hypothesis. This study is the first to demonstrate the biological relevance of ACE2-heme binding, uncover a new pathway of heme-dependent kidney injury, and identify myoglobin and heme as novel determinants of ACE2 expression. Our study explains why plasma levels of myoglobin and heme predict poor outcomes in patients with COVID-19.
Downloadable tool for modeling of salt, urea, and water transport in a renal tubule segment: application to the DCT.
Jayatissa NU, Sohail SK, Mejia R … +6 more , Murillo-de-Ozores AR, Khan S, Raghuram V, Chou CL, Yang CR, Knepper MA
Am J Physiol Renal Physiol · 2025 May · PMID 40106383 · Full text
We have devised a user-friendly downloadable, standalone application that solves a set of ordinary differential equations describing steady-state mass balance for salt (NaCl), urea, and water in a single renal tubule wit...
We have devised a user-friendly downloadable, standalone application that solves a set of ordinary differential equations describing steady-state mass balance for salt (NaCl), urea, and water in a single renal tubule with axial flow. The model was programmed in Python using an explicit ordinary differential equation solver. The standalone version allows users to interact with a graphical user interface to insert parameter values and initiate the calculations. It outputs volume flow rate and solute concentrations as a function of position along the tubule. We illustrate the use of the model to address questions about the roles of the mammalian distal convoluted tubule (DCT) in water balance. The simulations suggest an important role for the DCT as a second diluting segment beyond the cortical thick ascending limb (CTAL), consistent with a critical function in the excretion of water loads. Simulation of the effect of thiazide diuretics, which inhibit active salt absorption in the DCT, provides an explanation for the observation that these agents can produce hyponatremia when used clinically. The simulations also indicate that the DCT may transport salt in either direction (in accordance with micropuncture findings), depending on the salt concentration in the fluid entering from the CTAL. Salt reabsorption by active transport is balanced by passive salt secretion as the luminal salt concentration approaches an asymptotic "static head" level. The tool will allow users with no mathematical modeling experience to simulate transport in renal tubules, working toward the goal of expanding the use of mathematical modeling in physiology. The authors have created a downloadable, standalone computer application that solves a set of ordinary differential equations describing the transport of NaCl, urea, and water in a single renal tubule with axial flow. The tool will allow users with no mathematical modeling experience to simulate transport in renal tubules. The tool is applied to analysis of the distal convoluted tubule's role in water balance.
Toward a full-scale model of renal hemodynamics using a reconstructed vascular tree.
Xu P, Darkner S, Sosnovtseva O … +1 more , Holstein-Rathlou NH
Am J Physiol Renal Physiol · 2025 May · PMID 40099641 · Publisher ↗
The kidney's vascular network stands out because ) the microcirculation not only supplies the tissues with oxygen and nutrients but also supports glomerular filtration in each nephron, ) it contains the tubuloglomerular...
The kidney's vascular network stands out because ) the microcirculation not only supplies the tissues with oxygen and nutrients but also supports glomerular filtration in each nephron, ) it contains the tubuloglomerular feedback, a mechanism that contributes to renal blood flow autoregulation and is unique to the kidney, and ) the topology of the renal arterial network influences signaling along the vessels mediating nephron-nephron interactions. We have developed a full-scale vascular model of the rat kidney based on a reconstructed vascular network combined with a nephron model that includes glomerular filtration, tubular reabsorption, and autoregulation of afferent arteriolar resistances. The model evaluates the steady-state operating conditions of approximately 30,000 nephrons in a rat kidney and the efficiency of autoregulation under normal and pathological conditions. The simulation results show how the regulated afferent arteriolar resistances stabilize blood flow in the reconstructed full-scale renal vascular network. It is concluded that by using a reconstructed renal vascular tree, it is possible to develop a realistic full-scale model of the regulation of renal hemodynamics as a first step toward creating a virtual kidney. We have developed the first full-scale steady-state model integrating a realistic vascular network topology of the kidney and its hemodynamic regulatory mechanisms. The vascular network is combined with approximately 30,000 nephron models that include glomerular filtration, tubular reabsorption, and autoregulation of the afferent arteriolar resistances. By simulating the adaptive properties of the renal microcirculation at steady state, our approach demonstrates the feasibility of utilizing a reconstructed vascular network for comprehensive modeling of renal function.
Flow-dependent transport processes 2024: filtration, absorption, and secretion.
Edwards A, McDonough AA, Ellison DH
Am J Physiol Renal Physiol · 2025 May · PMID 40094947 · Full text
Fred S. Wright, an inaugural Associate Editor of , reviewed flow-dependent processes in the kidney in 1982. His elegant approach leveraged fundamental principles to show how blood flow through glomerular capillaries impa...
Fred S. Wright, an inaugural Associate Editor of , reviewed flow-dependent processes in the kidney in 1982. His elegant approach leveraged fundamental principles to show how blood flow through glomerular capillaries impacts glomerular filtration, how glomerular filtration rate affects reabsorption along the proximal tubule (the phenomenon of glomerulotubular balance), how flow into the thick ascending limb affects solute transport and luminal ion concentrations, and how flow along the distal tubule affects potassium secretion. In this review, we update those descriptions by introducing knowledge gained since that time regarding transport mechanisms and regulation. The goal is to build on the concepts that Wright introduced and provide a more comprehensive view, while retaining an approach based on first principles that is widely accessible.
Canagliflozin prevents acute kidney injury in euglycemic rats.
Ventura S, de Oliveira Silva E, Victoria CDP … +5 more , Vieira GHF, Villalba JPG, Lima C, Volpini RA, Vattimo MFF
Am J Physiol Renal Physiol · 2025 May · PMID 40079933 · Publisher ↗
The aim of this study was to investigate the impact of canagliflozin (CANA) on acute kidney injury (AKI) caused by ischemia-reperfusion injury (IRI) in nondiabetic rats. Male Wistar rats weighing 250-300 g were randomize...
The aim of this study was to investigate the impact of canagliflozin (CANA) on acute kidney injury (AKI) caused by ischemia-reperfusion injury (IRI) in nondiabetic rats. Male Wistar rats weighing 250-300 g were randomized into four groups: SHAM (rats subjected to sham renal ischemia-reperfusion surgery); CANA (canagliflozin by gavage, 200 mg/kg, once, daily, 5 days); ischemia-reperfusion (I/R): rats subjected to I/R-AKI (bilateral renal hilum clamping, 30 min); CANA + I/R: I/R rats that received canagliflozin 5 days before I/R. Evaluated parameters include renal function [serum creatinine (CrS), inulin clearance (inCl)]; renal hemodynamics [mean arterial pressure (MAP), renal blood flow (RBF), renal vascular resistance (RVR)]; redox profile [urinary peroxides, lipid peroxidation, urinary nitrate, renal tissue thiols, and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression], and Western blot for identification of sodium-glucose cotransporter 2 (SGLT2) in the kidneys and renal histology. Western blot essays confirmed the presence of SGLT2 in the kidneys. Regarding renal function in the animals subjected to IRI, an increase in CrS and a reduction in inCl were observed, whereas the group treated with CANA showed a reduction in CrS and an increase in inCl, demonstrating improved renal function after CANA treatment. Besides, canagliflozin pretreatment induced an improvement in renal hemodynamics and redox profile. Renal histology showed an increase in the tubular injury score in the IRI group, whereas canagliflozin was able to reduce tubular injury and inflammation in treated animals. Canagliflozin treatment prevented IRI-AKI, considering the methods used in this study. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of medications that act as glucose reducers in patients with type 2 diabetes mellitus. Recent studies have shown that SGLT2i also prevent acute kidney injury (AKI). The aim of this study was to investigate the impact of canagliflozin on ischemia-reperfusion (I/R)-induced AKI in nondiabetic rats.
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