American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
The many roles of the calcium-sensing receptor in the kidney.
Gutierrez-Gallardo MA, Bahena-Lopez JP, Ellison DH … +1 more , Gamba G
Am J Physiol Renal Physiol · 2026 May · PMID 41886276 · Publisher ↗
The calcium-sensing receptor (CaSR) is a central regulator of renal mineral homeostasis and tubular function. Since the discovery of its expression in the kidney, numerous studies have demonstrated that its actions are f...
The calcium-sensing receptor (CaSR) is a central regulator of renal mineral homeostasis and tubular function. Since the discovery of its expression in the kidney, numerous studies have demonstrated that its actions are finely distributed along the nephron. Through these segment-specific mechanisms, the CaSR orchestrates diverse physiological processes: contributes to the integrity of the filtration barrier, regulates proximal and distal tubular handling of essential ions such as calcium, magnesium, and sodium, and influences water transport and acid-base balance, integrating mineral metabolism with overall renal function. Collectively, these functions establish the CaSR as a key integrator of nephron physiology, linking calcium sensing to ion transport, cellular signaling, and renal protection under both physiological and pathological conditions.
Stimulation of basolateral calcium-sensing receptor inhibits Kir4.1/Kir5.1 in the mouse distal convoluted tubule.
Wang J, Zhang J, Kong S … +5 more , Ma P, Zhang Z, Wang L, Wang WH, Gu RM
Am J Physiol Renal Physiol · 2026 May · PMID 41886268 · Full text
The calcium-sensing-receptor (CaSR) is expressed in the basolateral membrane of distal convoluted tubule (DCT) and CaSR expression inhibited Kir4.1 in cells expressing . The aim of the study is to explore whether CaSR in...
The calcium-sensing-receptor (CaSR) is expressed in the basolateral membrane of distal convoluted tubule (DCT) and CaSR expression inhibited Kir4.1 in cells expressing . The aim of the study is to explore whether CaSR inhibits Kir4.1/Kir5.1 in mouse DCT. We used patch-clamp technique to examine the effect of calcimimetics and increasing extracellular Ca level on the basolateral Kir4.1/Kir5.1 in the DCT. Application of R-568, a CaSR agonist, decreased the 40-pS inwardly rectifying-K channel activity (Kir4.1/Kir5.1 heterotetramer), defined by NP (product of channel number and open probability), in the isolated DCT measured with cell-attached patches. This effect was completely abolished in the DCT treated with phospholipase-C (PLC) inhibitor or protein kinase C (PKC) inhibitor, suggesting that CaSR stimulation-induced inhibition of 40-pS K channel was due to activation of PLC-PKC pathway. Also, neomycin mimicked the effect of R-568 on the basolateral 40-pS K channel and decreased the 40-pS K channel activity. Again, this effect was completely abolished in the DCT treated with calphostin-C. Raising extracellular Ca level to 5 mM reversibly inhibited the 40-pS K channel activity of the DCT and the washout was able to partially restore the channel activity. Moreover, the inhibition of PKC was able to completely abolish the inhibitory effect of 5 mM Ca on the basolateral Kir4.1/Kir5.1 in the DCT. Finally, stimulation of CaSR with neomycin depolarized DCT cell membrane. We conclude that the activation of basolateral CaSR in the DCT inhibits Kir4.1/Kir5.1 and the effect of basolateral CaSR on the K channel is mediated by PLC-PKC pathway. It is not known whether CaSR also inhibits Kir4.1/Kir5.1 in the native DCT. We have now used the patch-clamp experiments to directly demonstrate that the stimulation of CaSR in the basolateral membrane is able to inhibit Kir4.1/Kir5.1 in the mouse DCT and depolarize the DCT membrane potential. We speculate that the stimulation of CaSR-induced inhibition of Kir4.1/Kir5.1 may play a role in decreasing kidney Ca excretion during hypocalcemia.
Increasing plasma sodium with Tolvaptan under regulated water intake: comparison with hypertonic saline.
Sweis NW, Tuazon J, Cheema Y … +3 more , Rosa R, Batlle D, Robertson G
Am J Physiol Renal Physiol · 2026 May · PMID 41886260 · Publisher ↗
In the treatment of hyponatremia, there is a potential risk of osmotic demyelination due to an excessively rapid rise in plasma sodium. We reasoned that a controlled rate of sodium increase could be achieved using a vaso...
In the treatment of hyponatremia, there is a potential risk of osmotic demyelination due to an excessively rapid rise in plasma sodium. We reasoned that a controlled rate of sodium increase could be achieved using a vasopressin antagonist like Tolvaptan while regulating water intake by under-replacing urine output by a constant amount relative to body weight. Studies were conducted in healthy male subjects in a clinical research unit to determine the effect of either 60 mg ( = 6) or 30 mg ( = 6) of Tolvaptan on plasma sodium, osmolality, plasma arginine vasopressin, thirst, and urine volume and osmolality. To regulate water intake, each subject ingested a volume of water equal to his urine output minus 5 mL/kg of his basal body weight every hour. Ten to 14 days later, the same subjects underwent a 6-h infusion of 3% saline, and the data were compared with the results with Tolvaptan. Both doses of Tolvaptan lowered urine osmolality and markedly increased free water clearance and urine output. Plasma sodium increased from 138 ± 0.6 to 144 ± 2.0 mEq/L and from 139 ± 0.8 to 144 ± 2.2 with Tolvaptan 60 and 30 mg, respectively, over 6 h of regulated water intake. When the same subjects were infused with hypertonic saline, the rise in plasma sodium and osmolality was nearly identical to that produced by Tolvaptan under regulated water intake. Tolvaptan can be used to achieve a controlled rise in plasma sodium by regulating water intake. Subjects with hyponatremia may benefit from this approach, which reduces their excess body water and is therefore a more physiologic way to correct hyponatremia. This study shows that the rise in plasma sodium induced by the vasopressin V2-receptor antagonist Tolvaptan can be controlled by regulating water intake to under-replace urine output by a fixed amount per kilogram body weight in healthy subjects. This approach produced increases in plasma sodium that were comparable to hypertonic saline and provides a means to prevent rapid rises in plasma sodium beyond the target rate.
Characterization of α, β, and muscarinic receptor distribution in porcine ureters: a translational model for pharmacological ureteral dilation.
Pham V, Rivero M, Gundogdu AT … +10 more , Ruiz-May C, Lawrence S, Gundogdu G, Gao B, Jiang P, Patel R, Landman J, Mauney J, Clayman RV, Wu YX
Am J Physiol Renal Physiol · 2026 May · PMID 41875023 · Publisher ↗
Intraoperative ureteral dilation through smooth muscle relaxation is of interest for improving upper urinary tract access during retrograde intrarenal surgery. Porcine ureters are widely used translational models due to...
Intraoperative ureteral dilation through smooth muscle relaxation is of interest for improving upper urinary tract access during retrograde intrarenal surgery. Porcine ureters are widely used translational models due to their anatomical similarities to humans; however, the distribution of receptors essential for pharmacological feasibility studies has not been fully characterized. This ex vivo study defines the regional expression of adrenergic and muscarinic receptors throughout the porcine ureter. Ureters from juvenile female Yorkshire swine ( = 4) were segmented into renal pelvis, proximal, middle, distal, and bladder cuff regions. Immunohistochemical (IHC) and histomorphometric analyses evaluated protein expression of α- and β-adrenergic receptor subtypes and muscarinic (M) subtypes. Quantitative-PCR assessed mRNA expression across ureteral regions; statistical analyses were performed using the Kruskal-Wallis test (IHC) and the Friedman test (qPCR), with Dunn's post hoc correction ( < 0.05). IHC demonstrated uniform distribution of α-, β-, M3, and M5 subtypes ( > 0.05). M1 expression was significantly higher in distal and bladder cuff regions versus proximal ureter ( = 0.0262), while M2 was elevated in the renal pelvis ( = 0.0134). All subtypes showed lower proximal immunoreactivity, and M4 was scantily detected. Most receptors are localized to the urothelium, except M3, which was also present in smooth muscle. qPCR confirmed expression of all receptor families except M4, with no regional differences in α-adrenergic or muscarinic transcripts. β-2 expression exceeded β-3 ( = 0.0439), and β-adrenergic transcripts were significantly higher than muscarinic ( = 0.0429). These results provide essential biological context for advancing translational research on the ureter. This study provides the first comprehensive quantitative characterization of adrenergic and muscarinic receptor distribution throughout the porcine ureter using qPCR and immunohistochemistry. Novel findings include the first quantification of all β-adrenoceptor subtypes, revealing β-2 dominance (74% of β-receptors, 54% of total transcripts), and detection of M1 muscarinic receptor mRNA. α-1a/1d codominance mirrors human ureters. Predominant urothelial receptor localization suggests epithelial smooth muscle signaling. These data strengthen the understanding of porcine ureteral physiology for clinical and translational studies.
Spoti-find: a novel, open-source void spot assay image analysis tool.
Hardy CC, Sheehan S, Mawe S … +4 more , Sebasco N, Ricke W, Mahoney M, Korstanje R
Am J Physiol Renal Physiol · 2026 May · PMID 41874957 · Full text
The void spot assay (VSA) is a widely used, noninvasive method for evaluating urinary behavior in rodents, but existing analysis tools are limited in scope, throughput, or accessibility. We developed Spoti-find, a stand-...
The void spot assay (VSA) is a widely used, noninvasive method for evaluating urinary behavior in rodents, but existing analysis tools are limited in scope, throughput, or accessibility. We developed Spoti-find, a stand-alone, open-source VSA image analysis application that introduces novel, biologically meaningful metrics including void circularity, distance to paper edge, and volume-based binning into primary, micro-, and nanovoids. Designed with usability in mind, Spoti-find features a graphical interface that enables manual or semiautomated spot identification, adjustable thresholds, and streamlined data export without the need for coding expertise. We validated Spoti-find across diverse datasets, showing strong interuser consistency, sensitivity to known phenotypes in aging and disease models, and accuracy in capturing novel parameters while demonstrating high agreement with existing tools. By capturing behavioral context and spatial morphology in voiding patterns, Spoti-find expands the interpretive power of VSA and provides a flexible, user-friendly platform for phenotyping urinary dysfunction in preclinical studies. The VSA is a popular, noninvasive method for studying rodent urinary behavior, but current tools lack flexibility and require extensive manual quality control. We developed Spoti-find, an open-source application introducing novel parameters like void circularity, edge proximity, and volume-based binning. With a user-friendly interface requiring no coding, Spoti-find enables manual and semiautomated analysis with high consistency and transparency.
Correction for Trott et al., volume 315, 2018, p. F1855-F1868.
Am J Physiol Renal Physiol · 2026 Apr · PMID 41870405 · Publisher ↗
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Correction for Hamatani et al., volume 330, 2026, p. F269-F284.
Am J Physiol Renal Physiol · 2026 Apr · PMID 41870404 · Publisher ↗
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Ovarian hormones moderate systolic hypertension in female haploinsufficient mice.
Dixon AJ, Mohanty I, Kaur G … +2 more , McCormick JA, Osei-Owusu P
Am J Physiol Renal Physiol · 2026 May · PMID 41869856 · Full text
Hypertension is a hallmark of cardiovascular abnormalities associated with Williams syndrome (WS), a rare genetic disorder involving microdeletion of genes on human chromosome 7, including the elastin gene (). Heterozygo...
Hypertension is a hallmark of cardiovascular abnormalities associated with Williams syndrome (WS), a rare genetic disorder involving microdeletion of genes on human chromosome 7, including the elastin gene (). Heterozygous deletion of () in mice recapitulates hypertension and arteriopathy associated with WS. Previously, differences in blood pressure elevation and sensitivity to dietary sodium were found to be less profound in female mice. Here, we determined whether ovarian hormones play a role in sex-related differences in blood pressure elevation resulting from haploinsufficiency. Female and mice instrumented with radiotelemetry devices were subjected to sham surgery or ovariectomy (OVX). We found that OVX lowered diastolic but not systolic blood pressure (SBP) in mice, resulting in increased pulse pressure. In mice, diuresis induced by acute volume expansion was blunted, whereas antinatriuresis was exaggerated. Furthermore, amiloride lowered SBP and increased urinary Na excretion, suggesting that -induced hypertension may be Na-dependent. We conclude that increased Na and water retention by the kidney contribute to hypertension resulting from haploinsufficiency. The underlying mechanism involves the alteration of ovarian hormone effects in the kidney and sustained signaling downstream of the V receptor, leading to increased epithelial sodium channel (ENaC) activity and water reabsorption. This study uncovers novel renal mechanisms by which haploinsufficiency leads to systolic hypertension and the role of ovarian hormones in moderating blood pressure elevation. In female haploinsufficient mice, ovarian hormone depletion elevates systolic blood pressure. haploinsufficiency augments sodium and water reabsorption that is, in part, mediated by sustained activity of the vasopressin V receptor and is associated with ENaC-dependent blood pressure elevation. These findings implicate abnormal sodium and water handling by the kidney as a contributing mechanism besides arteriopathy as the primary drivers of hypertension resulting from haploinsufficiency.
Fibroblast histone deacetylase-1 promotes kidney interstitial fibrosis following ischemia-reperfusion injury.
Nguyen H, Mendoza LD, Oliver AS … +5 more , Aldaz KJ, Montgomery AD, Kasztan M, Bolisetty S, Hyndman KA
Am J Physiol Renal Physiol · 2026 Apr · PMID 41830491 · Full text
Interstitial fibrosis is a hallmark of chronic kidney disease, and extracellular matrix is secreted by kidney fibroblasts/pericytes that have differentiated into myofibroblasts. Class I histone deacetylases (HDACs) are h...
Interstitial fibrosis is a hallmark of chronic kidney disease, and extracellular matrix is secreted by kidney fibroblasts/pericytes that have differentiated into myofibroblasts. Class I histone deacetylases (HDACs) are highly expressed in the nucleus of kidney cells, where they regulate transcription. Class I HDAC inhibitors prevent interstitial fibrosis in preclinical models of acute kidney injury (AKI). In the warm bilateral ischemia-reperfusion injury (IRI) model, HDAC1 was the only class I HDAC with greater protein abundance following IRI, including in interstitial cells. Thus, it was hypothesized that fibroblast/myofibroblast HDAC1 activation is profibrotic. ; hemizygous (iFibHDAC1KO) mice and (control) were given tamoxifen to induce Cre activity 3 wk before warm bilateral IRI or sham surgeries (preventative strategy). The severity of AKI was similar at 24 h postsurgery among the IRI mice, but glomerular rate filtration recovered over the 4-wk study. Despite this, only control male IRI mice developed progressive interstitial fibrosis and tubular injury, which was accompanied by increased kidney myofibroblasts. All the female mice were protected from developing fibrosis with this IRI model. Cultured kidney fibroblasts (NRK49F) overexpressing HDAC1 and/or differentiated to myofibroblasts with transforming growth factor-β1 had a significant shift in the cell cycle from G1 to S and G2 phases and increased proliferation. The HDAC1 overexpressing cultured fibroblasts had increased cell cycle/proliferation and proinflammatory transcriptomes. Indeed, control IRI male mice had significantly greater kidney CD3 and F4/80 immune cells 24 h postinjury compared with iFibHDAC1KO IRI mice. In conclusion, HDAC1 activation in the kidney fibroblast is profibrotic. This study identified kidney fibroblast HDAC1 as being profibrotic following ischemia and reperfusion in male mice. This epigenetic regulator promotes fibroblast/myofibroblast expansion in the kidney and in cultured fibroblasts. Fibroblast HDAC1 activation caused gene expression of proinflammatory cytokine/chemokines, and knocking down fibroblast HDAC1 in vivo was associated with reduced kidney immune cell infiltration. Thus, preventing fibroblast HDAC1 activation before acute kidney injury can slow the development of kidney interstitial fibrosis.
Glomerular hyperfiltration and enhanced sensitivity to kidney ischemia reperfusion with a blunted KIM-1 response in young male aging-accelerated SAMP8 mice.
Goodluck HA, Kanoo S, Kim YC … +5 more , Lopez N, Oe Y, Currais AJM, Maher P, Vallon V
Am J Physiol Renal Physiol · 2026 Apr · PMID 41830488 · Full text
To better understand the impact of accelerated aging on kidney function, we compared standard C57BL6 mice (C57BL6) with senescence-accelerated mouse-prone 8 mice (SAMP8). Young male SAMP8 (3 and 6 mo) showed glomerular h...
To better understand the impact of accelerated aging on kidney function, we compared standard C57BL6 mice (C57BL6) with senescence-accelerated mouse-prone 8 mice (SAMP8). Young male SAMP8 (3 and 6 mo) showed glomerular hyperfiltration compared with C57BL6 (absolute and per body weight), followed by gradual glomerular filtration rate (GFR) decline, lower blood pressure, and enhanced mortality over the first 15 mo of life. This was associated with higher kidney, heart, and liver but not brain weights. Female SAMP8 likewise showed a faster early rise in body weight, higher organ weights, and a somewhat higher mortality, but GFR and blood pressure appeared unaltered versus C57BL6. Since GFR phenotype was stronger in male mice, they were subjected to bilateral renal artery clamping-induced kidney ischemia reperfusion (IR). One day after IR, young SAMP8 (3 mo) showed higher plasma creatinine and kidney VCAM1 expression and subsequent mortality but a blunted rise in kidney mRNA and urine KIM-1 versus C57BL6. Kidney proteomics indicated suppressed pathways of phagocytosis and apoptosis but enhanced necroptosis in SAMP8 versus C57BL6. When ischemia time was lowered in SAMP8 to induce a similar initial rise in plasma creatinine and urine NGAL versus C57BL6, plasma creatinine recovery over 24 days was similar between strains in young mice, and despite impaired plasma creatinine recovery in older SAMP8 (10 mo) kidney injury or inflammation seemed not enhanced. In conclusion, male SAMP8 mice have a shortened life span, large kidneys, and at young age temporal hyperfiltration and enhanced sensitivity to IR-induced acute kidney injury associated with a blunted KIM-1 response. The impact of accelerated aging on kidney function is incompletely understood. The current work shows that male mice of an accelerated aging mouse strain have a shortened lifespan that is associated with large kidneys. At young age, the mice have temporal glomerular hyperfiltration, reminiscent of the early diabetic kidney, and show enhanced sensitivity to renal ischemia reperfusion-induced acute kidney injury associated with a blunted upregulation of the tubular injury marker KIM-1.
Reproducing human diabetic nephropathy in a novel obesity-driven animal model.
Teixidó-Trujillo S, Porrini E, Toniolo MF … +7 more , Luis-Lima S, Díaz-Martín L, Rodríguez-Rodríguez R, Menéndez-Quintanal LM, Torres-Ramírez A, Fumero C, Rodríguez-Rodríguez AE
Am J Physiol Renal Physiol · 2026 Apr · PMID 41758655 · Publisher ↗
Diabetic nephropathy is a leading cause of end-stage kidney disease worldwide, yet its complex pathogenesis remains incompletely understood. This is partly due to limitations of existing preclinical models, which are oft...
Diabetic nephropathy is a leading cause of end-stage kidney disease worldwide, yet its complex pathogenesis remains incompletely understood. This is partly due to limitations of existing preclinical models, which are often genotypic, monogenic, and fail to replicate the chronic progression and advanced renal damage observed in humans. We previously developed a nongenotypic rat model of type 2 diabetes model using obese male Sprague Dawley rats chronically treated with low-dose tacrolimus, which reproduced key metabolic features of human type 2 diabetes. In this study, we investigated the onset and progression of diabetic nephropathy in this model. Glomerular filtration rate was measured by iohexol-dried blood sample (DBS) plasma clearance. Twenty-four-hour urine collection was performed to assess albuminuria and proteinuria. At the endpoint, kidneys were collected for histological evaluation. Tacrolimus blood levels were monitored monthly. Diabetic animals initially exhibited glomerular hyperfiltration, followed by a decline in glomerular filtration rate at the final stage of the study, consistent with the trajectory observed in humans. This was accompanied by a trend toward increased proteinuria. Histological analysis revealed mesangial matrix expansion, a higher incidence of glomeruli with focal segmental glomerulosclerosis and significant glomerular hypertrophy. In addition, we observed increased kidney weight, tubular hypertrophy, intraglomerular and tubulointerstitial fibrosis, and elevated cortical expression of proinflammatory markers. This model reproduced both early and advanced pathological features of human diabetic nephropathy, representing a valuable tool for studying diabetic nephropathy pathophysiology in a chronic context and as a platform for evaluating potential therapeutic strategies. We present a nongenotypic, obesity- and tacrolimus-induced rat model that recapitulates the chronic progression of human diabetic nephropathy. The model reproduces key early and advanced features, including hyperfiltration, glomerular filtration rate (GFR) decline, glomerular hypertrophy, mesangial expansion, nodular sclerotic lesions, and tubular-interstitial fibrosis. Its translational relevance and long-term progression provide a valuable platform for mechanistic studies and for evaluating potential therapeutic strategies.
Acute kidney injury biomarker responses in young and older female adults following mild hypohydration.
Domeier C, Robinson AT, Babcock MC … +5 more , Vondrasek JD, Bissen TG, Muñoz CX, Smith KA, Watso JC
Am J Physiol Renal Physiol · 2026 Apr · PMID 41758613 · Full text
Hypohydration reduces kidney function and increases acute kidney injury (AKI) risk. Aging increases hypohydration-induced kidney dysfunction in males, but female aging studies are lacking. Therefore, we compared the effe...
Hypohydration reduces kidney function and increases acute kidney injury (AKI) risk. Aging increases hypohydration-induced kidney dysfunction in males, but female aging studies are lacking. Therefore, we compared the effects of mild hypohydration on kidney function and AKI biomarkers in young (YF) and older female adults (OF). In a random crossover design, 17 YF (20-35 yr old) and 9 OF (55-75 yr old), who were apparently healthy, completed two hydration protocols with ≥1 wk washout: ) baseline hydration, and ) stepwise water restriction over 3 days, concluding with 16 h water deprivation. We assessed hydration, AKI biomarkers, and the renin-angiotensin-aldosterone system (RAAS) from blood and 24-h urine samples. The effects of age group and condition were assessed using two-way mixed-effects analysis and reported as means ± SD. Hypohydration increased urine specific gravity and osmolality (condition effect: < 0.001) with no other main effects. Neutrophil gelatinase-associated lipocalin excretion decreased with hypohydration ( = 0.04), independent of age ( = 0.62). Urine cystatin C excretion increased in YF ( < 0.001) but not in OF ( = 0.69), with a significant interaction effect ( = 0.017). Nephrin excretion and product of urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 (IGFBP7 × TIMP-2) increased after hypohydration (both < 0.001), independent of age (both ≥ 0.35). OF exhibited lower plasma renin activity than YF ( = 0.046), with no other main or interaction effects for other RAAS markers. OF did not exhibit greater AKI biomarker responses to mild hypohydration, contrasting with male studies showing age-related kidney function decline. These results highlight the need for research to clarify potential sex-based differences in age-related decline in kidney function. This is the first study to assess the effects of mild hypohydration on acute kidney injury biomarkers in young and older female adults. Mild hypohydration altered acute kidney injury biomarker concentrations in both age groups, with no observed age-related differences, contrasting with male studies that show an age-related decline. These findings highlight the need for targeted research on potential sex-related differences in kidney function decline with aging.
Activation of farnesoid X receptor inhibits TMEM16A-mediated chloride secretion in renal collecting duct cells and retards renal cyst progression.
Srimai N, Tonum K, Sureram S … +3 more , Tubsuwan A, Kittakoop P, Soodvilai S
Am J Physiol Renal Physiol · 2026 Apr · PMID 41758537 · Publisher ↗
The farnesoid X receptor (FXR) plays a role in the regulation of renal transporters and ion channels. Our previous study reported that activation of FXR inhibited cystic fibrosis transmembrane conductance regulator (CFTR...
The farnesoid X receptor (FXR) plays a role in the regulation of renal transporters and ion channels. Our previous study reported that activation of FXR inhibited cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl secretion and retarded microcyst progression. The present study aims to investigate whether FXR regulates TMEM16A, a calcium-activated Cl channel that plays a major role in renal cyst progression in polycystic kidney disease (PKD). In vitro experiments were conducted to investigate the roles of FXR in TMEM16A-mediated Cl secretion and cyst progression using wild-type and -deleted collecting duct cells (mIMCD3 cells). In vivo experiments were performed in cystic polycystic kidney (PCK) rats. Treating collecting duct cells with FXR agonists (GW4064 and altenusin) decreased TMEM16A-mediated Clsecretion, an effect that required FXR activation. The inhibitory effect of FXR activation correlated with a reduction in TMEM16A protein levels. Decreased TMEM16A protein expression was associated with reduced mRNA expression and activation of lysosomal degradation pathways. GW4064 and altenusin retarded the enlargement of cysts derived from mIMCD3 cells, an effect attenuated by FXR inhibition. In cystic PCK rats, treatment with altenusin at doses of 7.5 and 15 mg/kg body wt significantly reduced the cystic index, kidney weight, blood urea nitrogen, and serum creatinine levels compared with vehicle-treated rats. These effects correlated with decreased TMEM16A expression in cystic kidneys. In addition, altenusin exhibited anti-inflammatory properties by attenuating the levels of inflammatory cytokines. This study highlights the role of FXR in regulating TMEM16A and in attenuating renal cyst progression, positioning FXR as a promising target for PKD treatment. Activation of farnesoid X receptor (FXR) downregulates TMEM16A-mediated Cl secretion in renal collecting duct cells. FXR stimulation reduces cyst enlargement in -deleted collecting duct cells and in PKD rats. The data support that FXR may be a candidate target for the treatment of autosomal dominant polycystic kidney disease.
NF-κB/Apaf1/caspase-9 axis suppresses autophagy to drive tubular inflammation and apoptosis in septic acute kidney injury.
Wang J, Li Z, Peng F … +2 more , Yan N, Liu Z
Am J Physiol Renal Physiol · 2026 Apr · PMID 41740623 · Publisher ↗
Septic acute kidney injury (AKI) is a life-threatening complication of systemic infection, characterized by rapid loss of renal function and high mortality. Despite its clinical significance, the underlying molecular mec...
Septic acute kidney injury (AKI) is a life-threatening complication of systemic infection, characterized by rapid loss of renal function and high mortality. Despite its clinical significance, the underlying molecular mechanisms remain incompletely elucidated. In this study, we identify the nuclear factor-κB (NF-κB)/apoptotic protease-activating factor 1 (Apaf1)/caspase-9 signaling axis as a central regulator of tubular apoptosis and inflammation through suppression of autophagy. Using proximal tubule-specific knockout mice, we demonstrate that deficiency significantly mitigates lipopolysaccharide (LPS)-induced renal dysfunction, reduces histopathological injury, and decreases tubular apoptosis, as evidenced by terminal deoxynucleotidyl transferase dUTP nick end labeling staining and cleaved caspase-3 expression. Correspondingly, renal inflammatory cytokines, including , , and , are markedly downregulated. In vitro, knockdown in LPS-treated BUMPT (the Boston University mouse proximal tubular cell line) cells similarly reduces apoptosis and inflammation, whereas overexpression exacerbates these pathological responses, confirming its pivotal role in tubular injury. Mechanistic studies reveal that Apaf1 mediates activation of caspase-9, which subsequently suppresses autophagic flux, as indicated by altered LC3 and p62 expression. Pharmacologic inhibition of caspase-9 using Z-LEHD-FMK restores autophagy, attenuates tubular apoptosis, and dampens inflammatory cytokine production in both cell culture and murine models, highlighting caspase-9 as a critical downstream effector. Furthermore, NF-κB functions as an upstream transcriptional activator of Apaf1, linking inflammatory signaling to autophagy suppression and tubular injury. Collectively, our findings delineate a sequential NF-κB/Apaf1/caspase-9/autophagy pathway that amplifies tubular inflammation and apoptosis in septic AKI. Targeting this axis may provide a novel therapeutic strategy to preserve tubular integrity, limit inflammation, and improve renal outcomes in patients with septic AKI. Our findings delineate a sequential NF-κB/Apaf1/caspase-9/autophagy pathway that amplifies tubular inflammation and apoptosis in septic AKI. Targeting this axis may provide a novel therapeutic strategy to preserve tubular integrity, limit inflammation, and improve renal outcomes in patients with sepsis-associated AKI.
Extracellular vesicle transcriptomes in human urine capture kidney adaptation to sodium intake.
Skov Jensen I, Zachar R, Jensen BL … +1 more , Svenningsen P
Am J Physiol Renal Physiol · 2026 Apr · PMID 41711484 · Publisher ↗
Urine extracellular vesicles (uEVs) originate from the genitourinary system, including the kidney's tubular epithelial cells. These cells control Na balance, for example, by increased aldosterone-induced Na reabsorption...
Urine extracellular vesicles (uEVs) originate from the genitourinary system, including the kidney's tubular epithelial cells. These cells control Na balance, for example, by increased aldosterone-induced Na reabsorption in response to a low-Na intake. We hypothesized that the uEV transcriptome reflects the physiological adaptation of tubular epithelial cells to variation in dietary Na. Paired biobanked uEV samples from healthy young men after 5 days on a low (70 mmol/day) and high (250 mmol/day) Na diet were analyzed by RNA sequencing. From 20 samples, 17 produced high-quality data, yielding quantitative data for >13,000 genes. The Na diets only significantly affected the uEV abundance of 10 gene transcripts; 5 decreased, and 5 increased, including , encoding the Na,Cl transporter NCC, in low-Na diet sample uEVs. We used transcriptomic deconvolution to estimate the uEVs' tissue and cell-type origins. The uEVs were mainly derived from the kidneys and bladder. Compared with the high-Na diet samples, the low-Na diet samples had a ∼30% higher kidney-derived uEV abundance. The estimated kidney-derived EV abundance was strongly correlated to plasma renin, plasma and urine aldosterone, and mean arterial blood pressure. At the kidney epithelial cell level, proximal tubule-derived EVs were most abundant. Although most of the cell-type-specific uEV abundances were not different between Na diets, β-intercalated cell-derived EVs were significantly less abundant in low-Na diet samples. Moreover, β-intercalated cell-uEV abundance estimates were negatively correlated with mean arterial pressure. In conclusion, uEV RNA analyses illuminate the pathways underlying physiological control of renal Na reabsorption in the human kidney. The kidneys adapt to changes in Na intake by regulating tubular Na transport, and we investigated whether the RNA content of urinary EVs (uEV) reflects the physiological responses to dietary Na intake in humans. Dietary Na intake altered both transcript abundance and kidney-derived uEV levels, which correlated with renin, aldosterone, and blood pressure levels. Thus, uEV transcriptomics provide a noninvasive window for studying the molecular control of kidney Na handling in humans.
Krüppel-like factor 2 regulates renin expression in mature juxtaglomerular cells.
Yamaguchi H, Smith JP, Guessoum O … +8 more , Daga D, Yamaguchi M, Almeida LF, Matsuoka D, Watanabe H, Medrano S, Gomez RA, Sequeira-Lopez MLS
Am J Physiol Renal Physiol · 2026 Apr · PMID 41711369 · Publisher ↗
Renin regulates blood pressure and fluid-electrolyte homeostasis via the renin-angiotensin-aldosterone system (RAAS), and renin cells function as renal baroreceptors that couple perfusion pressure to renin output. Krüppe...
Renin regulates blood pressure and fluid-electrolyte homeostasis via the renin-angiotensin-aldosterone system (RAAS), and renin cells function as renal baroreceptors that couple perfusion pressure to renin output. Krüppel-like factor 2 (Klf2), a canonical flow-responsive transcription factor, repeatedly emerged from our multiomics profiling linked to renin cell identity, but its role in renin cells remained unknown. We generated mice with renin-lineage-specific deletion (cKO: ) and assessed renin expression and kidney morphology. cKO mice showed reduced plasma renin at 2 mo that persisted at older ages, decreased mRNA, a lower juxtaglomerular renin area index by immunohistochemistry, and reduced carotid blood pressure, whereas the renal architecture and overall vasculature structure were largely conserved. Analysis of single-cell RNA-seq spanning progenitors to mature renin-lineage cells revealed low during embryogenesis and the neonatal period but enrichment in the mature postnatal juxtaglomerular cluster, consistent with a role in maintenance rather than early lineage specification. To test renin hypotensive stress and altered perfusion pressure, we challenged cKO mice with low-salt plus captopril and with surgical aortic coarctation (AoCo; right kidney high pressure, left kidney low pressure). In both models, plasma renin and cortical mRNA remained lower than in controls, and AoCo yielded a significantly blunted left-to-right ratio, indicating impaired pressure-responsive renin transcription. Together, the findings identify Klf2 as a transcriptional effector linking hemodynamic signals to renin transcription in mature juxtaglomerular cells. Identifying key transcriptional pathways in renin cells could reveal novel targets for modulating the RAAS and blood pressure. Using renin lineage cell-specific knockout mice, we identify Klf2 as a transcriptional effector linking hemodynamic pressure sensing to renin transcription in mature juxtaglomerular cells. Loss of blunted the upregulation of renin in response to low-salt/captopril and the pressure-responsiveness to low and high perfusion.
Injury-induced paracrine effects on the podocyte's transcriptome.
Zeng Y, Schweickart RA, Sharara J … +7 more , Maggiore JC, Loretz CJ, Hukriede NA, Pippin JW, Theberge AB, Wessely O, Shankland SJ
Am J Physiol Renal Physiol · 2026 Apr · PMID 41697116 · Full text
Although injury in glomerular disease might only damage a subset of podocytes in any given glomerulus, the response of the healthy neighboring podocytes to the injured podocytes oftentimes determines the course of the di...
Although injury in glomerular disease might only damage a subset of podocytes in any given glomerulus, the response of the healthy neighboring podocytes to the injured podocytes oftentimes determines the course of the disease. To investigate this relationship, we designed a dual-chamber open microfluidic coculture device to specifically examine paracrine signaling from podocytes undergoing targeted injury by either adriamycin, puromycin aminonucleoside, or a cytopathic antipodocyte antibody to healthy podocytes. Global transcriptomic analysis measured by RNA sequencing revealed shared and unique pathways between the three forms of targeted injury, with temporal differences in the transcriptomic responses to each form of injury. Transcriptional changes also showed that paracrine-induced injury to neighboring podocytes was similar to the targeted-injured podocytes and was specific for each podocyte injury model. In silico ligand-receptor analysis of ligands secreted by the insult-targeted podocytes and receptors expressed by the responsive, paracrine-injured counterparts identified 19 candidate mediator pairs that were shared among the three injury models. Several of these were enriched in patients with histological evidence of glomerular injury present in the Nephrotic Syndrome Study Network (NEPTUNE). One-factor-at-a-time candidate approaches validated the ability of these candidate pathways to mediate aspects of the podocyte injury models. Finally, an all-inclusive, comprehensive investigation of this signaling space using a systematic Design-of-Experiment analysis revealed that transforming growth factor-β1 (TGF-β1) signaling is a critical mediator of mitochondrial dysfunction during podocyte injury. Together, these findings define a new concept for future studies to understand the pathways involved in animal models and ultimately human studies. From a clinical perspective, it is ideal if yet unknown common pathways could be therapeutically targeted in different forms of injury in diseases of podocytes, and if there were mitigation strategies to minimize further damage to yet unaffected podocytes. The results of the current studies showed that there are indeed common responses to different experimental forms of podocyte injury and identified common paracrine signaling from injured podocytes that adversely affects the neighboring healthy podocyte population.
Kidney kallikrein-1 contributes to cleavage of γ-ENaC in vivo.
Curry JN, Su XT, Wu Q … +6 more , Maeoka Y, Yang CL, Delpire E, Fenton RA, Welling PA, Ellison DH
Am J Physiol Renal Physiol · 2026 Apr · PMID 41671061 · Full text
The epithelial sodium channel (ENaC) is essential for sodium reabsorption and potassium homeostasis in the distal nephron, where its activity is controlled by mineralocorticoid signaling and downstream proteolytic proces...
The epithelial sodium channel (ENaC) is essential for sodium reabsorption and potassium homeostasis in the distal nephron, where its activity is controlled by mineralocorticoid signaling and downstream proteolytic processing of channel subunits. Although cleavage of the γ-ENaC subunit has been implicated in aldosterone-mediated sodium transport, the identity of mineralocorticoid receptor (MR)-regulated proteases responsible for this process remains uncertain. Here, we investigated the role of kallikrein-1 (encoded by ), a serine protease expressed in the connecting tubule and cortical collecting duct (CNT/CCD), as a mediator of ENaC activation. Using CRISPR/Cas9, we generated a conditional -floxed allele and established mice with CNT/CCD-specific deletion of by crossing with -Cre (CNT-). On a low-sodium, high-potassium diet, CNT-mice exhibited ∼85% less renal kallikrein-1 expression, yet maintained normal serum electrolytes, urinary potassium excretion, and aldosterone responses. Western blot analysis revealed significantly less cleavage of γ-ENaC and α-ENaC in CNT- kidneys, accompanied by more total NCC abundance. Despite impaired ENaC proteolysis, amiloride-sensitive sodium excretion was preserved, indicating intact ENaC function. These findings identify renal kallikrein-1 as a protease that contributes to ENaC subunit processing in vivo. However, the absence of overt sodium or potassium handling defects in CNT- mice suggests that kallikrein-1 deficiency is not sufficient to disrupt overall ENaC function, likely due to compensatory mechanisms from redundant proteolytic or nonproteolytic pathways. Together, our results refine the role of kallikrein-1 as a modulator, rather than a sole determinant, of ENaC activation and highlight the complexity of aldosterone-dependent sodium transport in the distal nephron. Using a novel connecting tubule/cortical collecting duct specific kallikrein-1 knockout model, we show that γ- and α-ENaC cleavage is impaired by loss of renal kallikrein-1, without major disturbances in sodium or potassium handling. These findings highlight redundancy among ENaC regulatory pathways and suggest that proteolytic cleavage of ENaC, although useful as an indicator of ENaC-mediated transport under physiological conditions, may not, in and of itself, play a major role in ENaC function.
Making a portal for podocyte-parietal cell communication in glomerular injury.
Bruggeman LA
Am J Physiol Renal Physiol · 2026 Apr · PMID 41653085 · Full text
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Vascular transcriptional and metabolic changes precede progressive intrarenal microvascular rarefaction in autosomal dominant polycystic kidney disease.
Yilmaz G, Singha SK, Savaliya B … +9 more , Abdelfattah A, Elsekaily W, Xu X, Zhang Y, Hanna C, Hogan MC, Chade AR, Eirin A, Irazabal MV
Am J Physiol Renal Physiol · 2026 Mar · PMID 41643210 · Full text
The mechanisms contributing to progressive kidney damage in autosomal dominant polycystic kidney disease (ADPKD) remain unclear. Renal microvascular (MV) rarefaction plays an important role in kidney disease, but its nat...
The mechanisms contributing to progressive kidney damage in autosomal dominant polycystic kidney disease (ADPKD) remain unclear. Renal microvascular (MV) rarefaction plays an important role in kidney disease, but its natural history, underlying mechanisms, and contributions to renal disease progression in ADPKD remain unknown. We hypothesized that intrarenal MV rarefaction is present early on and is preceded by vascular transcriptional and metabolic changes. and wild type (WT) mice ( = 16 each) were studied at 1, 6, and 12 mo. Total kidney volume (TKV) was measured in vivo (MRI), whereas renal MV architecture [three-dimensional (3-D) micro-computed tomography, 3-D micro-CT], capillary density, perivascular fibrosis, and histomorphometric parameters were assessed ex vivo. In randomly selected and WT kidneys ( = 5, each/time point), mRNA-sequencing was performed to identify differentially expressed vasculature-related genes (differentially expressed genes, DEGs). Next, in young humans with ADPKD and matched controls ( = 10 each), plasma cellular energy metabolites were determined (LC-MS/MS), validated in an extended cohort ( = 32 and = 16, respectively), and correlated with markers of disease severity and progression. Gene-metabolite interaction networks were generated to integrate DEGs in at 1 mo with metabolites dysregulated in individuals with ADPKD, which were further quantified in WT and kidneys. Renal MV density was preserved at 1 mo but progressively decreased at 6 and 12 mo, associated with capillary loss and perivascular fibrosis. A total of 110, 48, and 201 DEGs were identified at 1, 6, and 12 mo, respectively. Plasma gamma-aminobutyric acid (GABA), homocysteine (Hcy), and asymmetric dimethyl arginine (ADMA) levels were higher in humans with ADPKD vs. controls, interacted with DEGs implicated in inflammatory and innate immune response and Hcy metabolism, and correlated with TKV and renal blood flow. Our data demonstrate that intrarenal MV abnormalities present early in ADPKD and are preceded by vascular transcriptional and metabolic changes. The renal microcirculation may constitute an important therapeutic target in ADPKD, and its underlying biomarkers may serve to monitor its progression. We provide the first longitudinal and most comprehensive analysis of the intrarenal microvasculature in a slowly progressive model of autosomal dominant polycystic kidney disease (ADPKD) and integrate the findings with studies in a young cohort of individuals with ADPKD. We identified vasculature-related pathways that could be targeted for therapeutic interventions and contribute promising, noninvasive biomarkers in patients with ADPKD. Alterations of the intrarenal microcirculation may affect drug delivery; a better understanding of its longitudinal changes may aid in treatment management.
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