American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
The transcription factor Tcf21 is necessary for adoption of cell fates by stromal progenitors during kidney development.
Finer G, Yacu GS, Khan MD … +10 more , Zhou Y, Gadhvi G, Ward SE, Sayed M, Gomez RA, Sequeira-Lopez MLS, Park JS, Lim HW, Quaggin SE, Winter DR
Am J Physiol Renal Physiol · 2026 Apr · PMID 41632505 · Full text
The stromal compartment of the developing kidney arises from forkhead box D1 (Foxd1)-expressing progenitors and gives rise to diverse cell types essential for nephrogenesis, including the renal stroma, capsule, mesangial...
The stromal compartment of the developing kidney arises from forkhead box D1 (Foxd1)-expressing progenitors and gives rise to diverse cell types essential for nephrogenesis, including the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs). However, the molecular mechanisms guiding their fate specification remain incompletely defined. Here, we identify the basic helix-loop-helix transcription factor Tcf21 as a critical determinant of stromal cell identity during kidney development. We performed single-cell RNA sequencing (scRNA-seq) on Foxd1-lineage cells isolated from embryonic (E14.5) Tcf21 conditional knockout (-cKO) ;; and control kidneys, revealing seven transcriptionally distinct stromal subpopulations. Loss of Tcf21 resulted in marked depletion of medullary/perivascular stroma, collecting duct-associated stroma, proliferating stroma, and nephrogenic zone-associated subpopulations, confirmed by immunostaining, which revealed severe constriction of medullary and collecting duct stromal spaces. In addition, we identified a novel cluster unique to cKO kidneys, characterized by high expression of endomucin (Emcn). These cells spanned pseudotime trajectories and were distributed broadly across the mutant kidney. These findings were corroborated by E14.5 single-cell ATAC sequencing (scATAC-seq), which confirmed altered chromatin accessibility in Tcf21-deficient stroma. To assess the persistence and downstream impact of these defects, we performed bulk and scRNA-seq at E18.5, revealing sustained expansion of Emcn cells with profibrotic and perivascular transcriptional programs. Histological analyses at 2 mo demonstrated lasting architectural disruption, interstitial fibrosis, and impaired renal function in cKO mice. Our results identify Tcf21 as a key regulator of stromal progenitor fate and establish a developmental origin for fibrotic remodeling and kidney dysfunction. This study identifies Tcf21 as a key regulator of kidney stromal fate. Loss of Tcf21 disrupts the emergence of key stromal cell types and leads to the expansion of a dysregulated, Emcn-expressing stromal population. Integrating single-cell transcriptomics, chromatin accessibility, and histology, we show that this misdifferentiation contributes to fibrosis in adulthood. These findings suggest that TCF21-dependent stromal differentiation restrains maladaptive remodeling and links developmental fate decisions to later fibrotic disease.
Hedgehog pathway disruption alters urothelial differentiation and continence mechanisms in the female mouse lower urinary tract.
Tanaka LF, Tlapa J, Morrison J … +11 more , Jordan T, Ridlon M, Ambrogi M, Kracke-Bock JA, Resende A, Eyman MS, Blosch CD, Peter J, Lipinski RJ, Farhat W, Keil Stietz KP
Am J Physiol Renal Physiol · 2026 Mar · PMID 41592753 · Full text
Urinary incontinence (UI) imposes a significant healthcare burden and reduces quality of life. Contributing factors such as aging, pregnancy/childbirth, stress, and injury are recognized, but incomplete understanding of...
Urinary incontinence (UI) imposes a significant healthcare burden and reduces quality of life. Contributing factors such as aging, pregnancy/childbirth, stress, and injury are recognized, but incomplete understanding of underlying mechanisms limits new therapies. Hedgehog (Hh) signaling has been implicated in lower urinary tract development, but its specific role in female continence mechanisms has not been fully characterized. Here we investigate the functional and molecular consequences of reduced Hh signaling using ; ( mutant) female mice. We assessed spontaneous voiding through void spot assays and uroflowmetry, then assessed contractility in bladder and urethral tissues ex vivo. Female mutant mice display more small volume voids than wild-type mice. mutant female bladder had reduced strength of contraction to electrical field and cholinergic stimuli, whereas the urethra had reduced sensitivity to serotonin-mediated contraction, but not to phenylephrine. Thus, unique changes to bladder and urethral contractility dynamics are present in mutant mice and are dependent upon types of stimuli. Furthermore, expression of serotonin transporter () mRNA was increased in mutant urethra compared with wild type. Uroplakin IIIa, typically localized to bladder urothelium, was ectopically expressed in distal urethral urothelium of adult but not embryonic (E) mutant mice. These findings highlight a previously uncharacterized role of Hh signaling in maintaining female lower urinary tract function and urothelial patterning, and support further investigation of its contribution to continence. This study identifies disrupted Hh signaling as a key determinant of female bladder and urethral contractility, providing new insights into molecular mechanisms maintaining continence. We observe impaired contractile responses to multiple stimuli, including urethral response to serotonin. In addition, we identify ectopic expression of uroplakin IIIa in urethra of mutant mice, arising after prenatal development. By reducing-but not completely ablating-Hh signaling, we elucidate essential roles of this pathway in determining continence.
Citrate modulates calciprotein particle formation and composition.
de La Roij G, van der Meijden RHM, Rutten L … +5 more , Hoogstraten CA, Hinnen M, Martens S, Hoenderop JGJ, de Baaij JHF
Am J Physiol Renal Physiol · 2026 Mar · PMID 41553722 · Publisher ↗
Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), partly due to phosphate-induced vascular calcification. Fetuin-A stabilizes calcium-phosphate complexes into calciprotein particles (CPPs),...
Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), partly due to phosphate-induced vascular calcification. Fetuin-A stabilizes calcium-phosphate complexes into calciprotein particles (CPPs), preventing precipitation, but CPPs can mature into crystalline particles that drive calcification, particularly in CKD. In this study, we investigated whether citrate, a calcium chelator, could mitigate CPP-induced vascular calcification in vitro. Vascular smooth muscle cells (VSMCs) were incubated with CPPs containing varying citrate concentrations. We quantified calcification using calcium assays and characterized CPPs using spectrophotometry, dynamic light scattering, cryogenic transmission electron microscopy (cryo-TEM), electron diffraction (ED), Raman spectroscopy, energy dispersive X-ray spectroscopy, and mass spectrometry (MS). The highest citrate concentration, reduced calcification by 88% versus standard CPPs ( < 0.0001). CPP maturation was delayed, and mean diameter was 9% lower (216 ± 2 nm vs. 236 ± 6 nm; = 0.0022). Cryo-TEM showed a transition from primary to secondary CPPs with preserved morphology. Hydroxyapatite was detected by ED in the standard and high-citrate CPPs, with the latter showing a significant lattice shift. An increased mineral-to-protein ratio was observed by Raman spectroscopy and protein-to-calcium assays. EDX demonstrated unchanged Ca/P ratios, but differences were observed in Ca ( = 0.0003), P ( < 0.0001), Na ( < 0.0001), and Cl ( < 0.0001). Finally, proteomics revealed 18 proteins enriched in standard CPPs (fold-changes -1.2 to -3.4; FDR < 0.05), including lipid-related apolipoproteins APOM, APOA1, APOA2, APOC3, and APOE. These data indicate that citrate remodels CPPs toward a less calcifying phenotype, highlighting its potential as a therapeutic strategy against vascular calcification in CKD. We show for the first time that CPPs can be directly modulated by incorporating citrate during their formation. Citrate-modified CPPs maintain their hydroxyapatite core but display altered crystall lattice structure, reduced size, and changes in protein composition with fewer apolipoproteins. Importantly, they induce 88% less calcification in VSMCs. These findings provide proof-of-principle that CPP remodeling may represent a novel therapeutic strategy to limit vascular calcification in CKD, warranting further investigation in vivo.
Loss of transcription factor ATOH8 activates TGF-β signaling and exacerbates glomerulosclerosis in podocytes.
Hamatani H, Tabei A, Ogawa S … +9 more , Suwa J, Ishihara R, Murakami Y, Sakairi T, Ikeuchi H, Kaneko Y, Handa H, Morikawa M, Hiromura K
Am J Physiol Renal Physiol · 2026 Feb · PMID 41545031 · Publisher ↗
Atonal BHLH transcription factor 8 () is a basic helix-loop-helix (bHLH) transcription factor; however, its role in glomerular epithelial cells (podocytes) remains unclear. This study aimed to elucidate the function of A...
Atonal BHLH transcription factor 8 () is a basic helix-loop-helix (bHLH) transcription factor; however, its role in glomerular epithelial cells (podocytes) remains unclear. This study aimed to elucidate the function of ATOH8 in podocytes. First, ATOH8 expression in the mouse kidney was confirmed in podocytes by immunofluorescence staining and in situ hybridization. In cultured human podocytes, transforming growth factor-beta (TGF-β) treatment significantly reduced mRNA expression. To examine the functional consequences of ATOH8 downregulation, expression was knocked down with shRNA. Subsequent RNA sequencing analysis of -knockdown podocytes revealed increased extracellular matrix gene expression and activation of TGF-β signaling. -knockdown podocytes also showed SMAD2/3 nuclear translocation, increased SMAD transcriptional activity, as determined by a luciferase assay, and upregulated mRNA even without TGF-β stimulation, consistent with TGF-β signaling activation. In vivo, C57BL/6 -deficient mice showed no renal abnormalities at baseline. However, in an adriamycin (ADR)-induced focal segmental glomerulosclerosis (FSGS) model, -deficient mice developed significantly more severe glomerulosclerosis than wild-type mice, with higher renal cortical and mRNA levels. Reduced ATOH8 expression was also observed in ADR-induced nephropathy in mice and rats and in various human glomerular diseases. These findings suggest that ATOH8 downregulation enhances TGF-β signaling and glomerulosclerosis progression, indicating a protective role for ATOH8 in maintaining podocyte integrity and preventing kidney injury. This study identifies atonal transcription factor 8 (ATOH8) as a previously unexplored regulator of podocyte function. We demonstrate that ATOH8 knockdown activates TGF-β signaling and increases extracellular matrix gene expression. Notably, ATOH8 deficiency alone does not cause renal injury but exacerbates glomerulosclerosis in an adriamycin-induced nephropathy model, accompanied by increased mRNA expression in the renal cortex. These findings indicate that ATOH8 plays a protective role in podocyte function and limits glomerulosclerosis during kidney injury.
Using the intravesical delivery route to target the kidney.
Wang X, Hu H, Wang Q … +2 more , Li L, Shen XZ
Am J Physiol Renal Physiol · 2026 Feb · PMID 41545021 · Publisher ↗
Despite advances in drug delivery technologies, there is still an unmet demand for noninvasive kidney-targeted drug delivery systems that enhance therapeutic efficacy while minimizing systemic side effects. In the presen...
Despite advances in drug delivery technologies, there is still an unmet demand for noninvasive kidney-targeted drug delivery systems that enhance therapeutic efficacy while minimizing systemic side effects. In the present study, we conducted a proof-of-concept study to evaluate the feasibility and effectiveness of intravesical delivery as a kidney-targeting strategy in mice. We demonstrated that intravesical infusion could retrogradely deliver molecules with a size up to 500 kDa to both the medulla and cortex of the kidney. In particular, empagliflozin, an antagonist of sodium-glucose cotransporter 2 (SGLT2), could effectively target the uppermost segment of the renal tubular system, that is, the proximal tubules, when administered via the intravesical route, thereby promoting glucose excretion. In an orthotopic renal carcinoma model, intravesical delivery of a chemotherapeutic agent achieved superior tumor suppression with markedly reduced adverse effects on extrarenal organs, compared with systemic administration at an equivalent dose. This improvement was attributed to a higher renal drug concentration and substantially lower systemic exposure achieved by intravesical delivery, demonstrating its kidney-targeting specificity. Thus, these findings indicated that the intravesical delivery route offers a promising strategy for kidney-targeted therapy and related translational research. Intravesical infusion is valid for retrograde delivery of molecules up to 500 kDa to both the medulla and cortex of the kidney. This route is highly selective in targeting the urinary system with limited leakage to extrarenal organs, providing great potential as a noninvasive means for kidney-targeted research and therapy.
Processing of ENaC in mouse kidney: effects of aldosterone and a Liddle syndrome mutation.
Frindt G, Yang L, Rohan T … +1 more , Palmer LG
Am J Physiol Renal Physiol · 2026 Mar · PMID 41500518 · Full text
We investigated the interplay between the mineralocorticoid aldosterone and a mutation mimicking Liddle syndrome in the control of the processing of the epithelia Na channel (ENaC) in mouse kidneys. Rates of processing w...
We investigated the interplay between the mineralocorticoid aldosterone and a mutation mimicking Liddle syndrome in the control of the processing of the epithelia Na channel (ENaC) in mouse kidneys. Rates of processing were assessed by the appearance of the cleaved form of the γENaC subunit. Cleaved γENaC increased with decreasing dietary Na intake and with administration of aldosterone. Measurements taken from isolated tubules indicated that enhanced processing was similar in connecting tubules and in late distal convoluted tubules. In a mouse model with a truncated βENaC subunit (Liddle mice), levels of cleaved γENaC were similar in wild-type (WT) and Liddle animals. The amounts of the full-length form of the subunit were lower in the Liddle mice on control and high-Na diets. Infusion of a low dose of aldosterone produced similar increases in cleaved γENaC in WT and Liddle mice, whereas with maximal doses, levels in Liddle animals were 35% higher than in WT. Acute Na repletion of Na-depleted mice decreased cleaved γENaC with a time constant of 5 h. Rates of decrease were similar in WT and Liddle genotypes. The Liddle's mutation produces modest changes in ENaC processing, and a major effect of the mutation is on the activation of processed channels. Using a mouse model of Liddle syndrome we show that the effects of the mutation on ENaC activity do not correlate with effects on channel processing. We conclude that the hyperactivity of the channels likely results from increased activity of processed channels residing in the apical membrane.
The response to kidney injury is epigenetically regulated through the activation of bivalent genes.
Tickman BI, McDonald JR, McCarthy R … +8 more , Suh K, Okamura DM, Houghtaling SR, Collins SJ, Bae Y, Beier DR, Majesky MW, Nguyen ED
Am J Physiol Renal Physiol · 2026 Feb · PMID 41500515 · Full text
Epigenetic regulation through histone modifications plays a crucial role in driving cellular state transitions. Regulating gene transcription through bivalency, the co-occurrence of activating histone H3 lysine 4 trimeth...
Epigenetic regulation through histone modifications plays a crucial role in driving cellular state transitions. Regulating gene transcription through bivalency, the co-occurrence of activating histone H3 lysine 4 trimethylation (H3K4me3) and repressive histone H3 lysine 27 trimethylation (H3K27me3) histone marks, drives cell fate in development; however, its role in kidney injury is not known. Here, we investigated bivalent gene activation in the adult male kidney following ischemia-reperfusion injury (IRI). We developed and validated a novel per-gene scoring method for identifying bivalent domains from CUT&RUN (Cleavage Under Targets and Release Using Nuclease) data. Our analysis revealed that bivalent genes in the mature kidney substantially overlap with known embryonic bivalent domains. Following IRI, a subset of bivalent genes became activated, defined by a loss of H3K27me3, enrichment of H3K4me3, and a corresponding increase in gene transcription. Activated bivalent genes were differentially expressed in kidney epithelial cells and strongly enriched for pathways involving inflammation and fibrosis. To uncover the regulatory mechanism associated with activated bivalent genes, we identified key transcription factors linking these genes which converged on the pioneer transcription factor, . We demonstrated that targets are differentially expressed in both mouse and human kidney epithelial cells after injury and preferentially depleted of H3K27me3 and gain H3K4me3 enrichment after IRI, supporting its role in mediating the epigenetic switch. Our findings reveal a common epigenetic mechanism where transcription factors, acting on bivalent chromatin, contribute to inflammatory and fibrotic responses to kidney injury. This suggests that the progression from acute to chronic kidney injury is an active, transcriptionally driven failure of repair that is epigenetically mediated by histone modifications. We performed the first identification of bivalent domains in the adult mouse kidney. We identified bivalent genes that, when activated after kidney injury, drive inflammation, proliferation, and fibrosis. Activation of bivalent genes is coordinated by transcription factors such as . Our research not only provides a valuable database of bivalent genes in the kidney but also demonstrates that activation of bivalent genes is crucial for the progression from acute to chronic kidney injury.
Protective effects of fermentable dietary fiber and propionate in Dahl salt-sensitive hypertension and renal damage.
Walton SD, Dasinger JH, Burns-Ray EC … +8 more , Hartenburg LN, Baldwin KE, Lin J, Cherian-Shaw M, Tummala R, Joe B, Mattson DL, Abais-Battad JM
Am J Physiol Renal Physiol · 2026 Feb · PMID 41481281 · Full text
The Dahl salt-sensitive (SS) rat is an established model of hypertensive kidney injury, where the gut microbiota has been shown to causally contribute to disease progression. Gut bacteria-derived metabolites serve as mec...
The Dahl salt-sensitive (SS) rat is an established model of hypertensive kidney injury, where the gut microbiota has been shown to causally contribute to disease progression. Gut bacteria-derived metabolites serve as mechanistic links between the microbiota and disease, with dietary fiber providing a critical source of protective metabolites such as short-chain fatty acids (SCFAs). The current study hypothesized that the substitution of nonfermentable fiber cellulose with the fermentable fiber inulin would attenuate hypertension and renal damage in SS rats via increased circulating SCFAs. Male and female SS rats were placed on the 0.4% NaCl (low-salt, LS) inulin diet for 1 wk before the switch to a 4.0% NaCl (high-salt, HS) inulin diet for 4 wk. Controls were maintained on diets containing cellulose. Rats consuming inulin had a reduction in mean arterial pressure compared with cellulose, though the antihypertensive effect was more robust in females. The inulin diet significantly protected both sexes from albuminuria, medullary protein cast formation, and renal immune cell infiltration, and was associated with specific changes to the fecal microbiota. Assessed by mass spectrometry, inulin consumption resulted in increased circulating propionate and butyrate, and the administration of these SCFAs revealed a protective effect of propionate against salt-sensitive hypertension and kidney damage in males, which coincided with an expansion of renal T regulatory cells. In conclusion, substitution of cellulose for the fermentable fiber inulin lowered blood pressure and significantly attenuated salt-induced renal damage in both sexes, which may be attributed to greater production of the protective, anti-inflammatory SCFA propionate. The dietary switch to inulin, a fermentable fiber, reduced salt-sensitive hypertension and kidney injury in male and female Dahl SS rats, and caused gut microbiota composition shifts and increases in SCFA production (propionate and butyrate). Direct administration of propionate ameliorated salt-sensitivity in males, which coincided with renal T regulatory cell expansion. These findings provide the mechanistic basis for leveraging the microbiota and its metabolites through dietary interventions as a therapeutic for hypertension and kidney disease.
Rapid podocyte loss in murine models triggers the formation of podocyte-parietal epithelial cell intercellular bridges.
Cintron Pregosin N, Guo Y, Dang ET … +7 more , Gujarati NA, Revelo MP, Sheikh F, Hennigar RA, Salant DJ, D'Agati VD, Mallipattu SK
Am J Physiol Renal Physiol · 2026 Feb · PMID 41481276 · Publisher ↗
Podocytes are highly specialized, terminally differentiated visceral epithelial cells that are critical for the maintenance of the glomerular filtration barrier. In subtypes of glomerulonephritis and focal segmental glom...
Podocytes are highly specialized, terminally differentiated visceral epithelial cells that are critical for the maintenance of the glomerular filtration barrier. In subtypes of glomerulonephritis and focal segmental glomerulosclerosis (FSGS), injured podocytes trigger the activation and proliferation of neighboring parietal epithelial cells (PECs) which line Bowman's capsule. Mechanisms by which injured podocytes trigger the activation of PECs remain poorly understood. In three independent murine models of proliferative glomerulopathy, we observed that rapid podocyte loss triggered the formation of novel intercellular bridges (or tunneling nanotubes) extending between podocytes and PECs. Immunofluorescence staining of a coculture of mouse podocytes and PECs also revealed the presence of vesicle-like structures within intercellular bridges. In addition, these vesicle-like structures stained positive for Ras-related protein Rab-11A (RAB11A), a RabGTPase involved in the regulation of vesicle transport, and cytoplasmic dynein 1 heavy chain 1, a critical motor protein involved in cargo transport. Finally, we identified intercellular bridges in human kidney biopsies with subtypes of glomerulonephritis and collapsing FSGS, suggesting relevance to human disease. To date, this is the first study to demonstrate that intercellular bridges form between podocytes and parietal epithelial cells in the setting of rapid podocyte loss in subtypes of glomerulonephritis and FSGS.
Pendrin is upregulated by corticosterone and participates in its pressor response.
Pham TD, Abood DC, Delpire E … +9 more , Luther JM, Harris AN, Castro RA, Ferdaus MZ, Mullins LJ, Mullins JJ, Simmons A, Surendran K, Wall SM
Am J Physiol Renal Physiol · 2026 Feb · PMID 41452602 · Full text
NaCl restriction upregulates pendrin, in part, through increased circulating aldosterone and the intercalated cell (IC) mineralocorticoid receptor (MR). Since 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enhances a...
NaCl restriction upregulates pendrin, in part, through increased circulating aldosterone and the intercalated cell (IC) mineralocorticoid receptor (MR). Since 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enhances aldosterone binding to this receptor in other cells, we asked if pendrin abundance is reduced in NaCl-restricted 11β-HSD2 knockout (KO) rats. However, pendrin abundance was greater in 11β-HSD2 KOs than in controls, possibly from enhanced glucocorticoid MR activation. Moreover, the MR antagonist, spironolactone, reduced pendrin abundance in mice that do not produce aldosterone (aldosterone synthase KO). IC MR gene ablation also reduced pendrin protein abundance in corticosterone-treated, adrenalectomized mice. Therefore, the MR regulates pendrin independently of aldosterone. As such, we asked whether glucocorticoids, the other MR ligands, change pendrin abundance and/or subcellular distribution in adrenalectomized wild-type mice. We observed that corticosterone upregulated pendrin in a dose-dependent manner through both increased total protein abundance and subcellular redistribution. At higher doses, corticosterone increased pendrin abundance from greater pendrin-positive cell number within the late distal convoluted tubule 2 (DCT2) rather than increased pendrin abundance per cell. Finally, we asked whether pendrin contributes to the hypertension seen in rodent models of Cushing syndrome. Although corticosterone increased blood pressure in wild-type mice, it had no effect in pendrin KOs. In conclusion, glucocorticoids upregulate pendrin by increasing pendrin total protein abundance through an MR-dependent pathway and subcellular redistribution. Glucocorticoids increase pendrin abundance by increasing the number of pendrin-positive cells within the DCT2. In doing so, pendrin contributes to the hypertension seen in rodent models of Cushing syndrome. Pendrin participates in the hypertension seen in Cushing syndrome.
Obesity enhances salt-sensitivity of blood pressure, independent of skin electrolytes, and more in female than in male ZSF1 rats.
Nguyen ITN, Tenstad O, Samuelsson AM … +4 more , Wiig H, Hoorn EJ, Verhaar MC, Joles JA
Am J Physiol Renal Physiol · 2026 Feb · PMID 41432720 · Publisher ↗
Obesity and sex influence the salt-sensitivity of blood pressure, but it is unknown whether this also affects tissue electrolyte accumulation. We hypothesized that obese female rats exhibit greater salt-sensitivity of bl...
Obesity and sex influence the salt-sensitivity of blood pressure, but it is unknown whether this also affects tissue electrolyte accumulation. We hypothesized that obese female rats exhibit greater salt-sensitivity of blood pressure with higher nonosmotic sodium accumulation in skin compared with obese male or lean female rats. To investigate this, male and female lean and obese ZSF1 rats received either a deoxycorticosterone acetate (DOCA) pellet plus a high-salt diet (6% NaCl) or a placebo pellet plus normal salt diet at 19 wk of age. Systolic blood pressure (SBP) and 24-h sodium excretion were measured biweekly from 12 to 26 wk. At 26 wk, sodium and potassium content in the skin was measured. SBP was higher in obese than in lean rats within the DOCA + high-salt groups. Lean female rats showed no SBP increase in response to the DOCA + high-salt diet. Analysis of pressure-natriuresis curves confirmed that obesity increased the salt-sensitivity of blood pressure. Furthermore, there was a significant interaction between sex and obesity on salt-sensitivity of blood pressure: lean female rats were completely salt-resistant, whereas obese female rats showed the greatest salt-sensitivity of blood pressure. Similar trends were observed in males, but the effects were less pronounced. Despite differences in salt-sensitivity of blood pressure, there were no differences in skin electrolytes. In conclusion, obesity enhances salt-sensitive hypertension more in female than in male rats, independent of skin electrolytes. In the presence of obesity, salt-sensitivity of blood pressure was greater in female than in male ZSF1 rats, whereas in the absence of obesity, female rats were salt-resistant. Interestingly, these differences occurred without changes in sodium or potassium accumulation in the skin. These findings highlight that obesity leads to loss of female advantage in salt-sensitive hypertension and call into question the role of nonosmotic sodium storage in salt-sensitivity of blood pressure.
The association between extracellular fluid volume and sympathetic nervous system activity in patients with chronic kidney disease.
Jeong J, Bunsawat K, Sabino-Carvalho J … +9 more , Zanuzzi M, Mekonnen E, McGranahan M, Kamal F, DaCosta D, Dixon D, Lee I, Cui X, Park J
Am J Physiol Renal Physiol · 2026 Feb · PMID 41432718 · Full text
Chronic kidney disease (CKD) is associated with hypervolemia and sympathetic nervous system (SNS) overactivity that both contribute to heightened cardiovascular risk. Classically, extracellular fluid volume (ECFV) is inv...
Chronic kidney disease (CKD) is associated with hypervolemia and sympathetic nervous system (SNS) overactivity that both contribute to heightened cardiovascular risk. Classically, extracellular fluid volume (ECFV) is inversely related to SNS activity, whereby increased ECFV suppresses SNS activation. However, ECFV and SNS activity could be concomitantly elevated if there is failure to suppress SNS activity or if SNS activity plays a contributory role in ECFV expansion. Therefore, we examined the clinical determinants of increased ECFV, the association between ECFV and SNS activity, and whether kidney function accounts for this relationship in CKD. In this cross-sectional study, patients with stage II-IV CKD (62 ± 12 yr, 67% men, 90% with hypertension, = 104) underwent an assessment of ECFV via extracellular water/total body water ratio, using multifrequency bioimpedance, and a subset had SNS activity via muscle sympathetic nerve activity (MSNA, = 39). We examined linear associations between ECFV and clinical factors, including MSNA, and group comparisons of MSNA across ECFV tertiles. Multivariable regression analyses were used to assess the relative contribution of kidney function [i.e., estimated glomerular filtration rate (eGFR)] and MSNA to ECFV. ECFV was inversely associated with eGFR and positively associated with age, systolic blood pressure, and pulse pressure ( < 0.05 for all). MSNA was different across ECFV tertiles ( = 0.009), with higher MSNA in and compared with (41 ± 14 and 35 ± 12 vs. 26 ± 9 bursts/min, = 0.002 and 0.081, respectively), even after adjusting for eGFR, age, sex, and antihypertensive medications. MSNA ( = -0.376, = 0.018) was inversely associated with eGFR. In multivariable models, eGFR remained a significant predictor of ECFV (β = -0.341, = 0.045), whereas MSNA showed no independent association with ECFV (β = 0.124, = 0.457). An inverse relationship between ECFV and SNS activity is not observed in stage II-IV CKD; rather, MSNA is higher in patients with higher ECFV. These findings suggest that the sympathoexcitatory effects of reduced kidney function may override the sympathoinhibitory effects of increased ECFV in CKD. Patients with chronic kidney disease (CKD) face high cardiovascular risk from both fluid overload and heightened sympathetic nervous activity. In healthy individuals, fluid expansion suppresses sympathetic tone; however, this inverse relationship was absent in our cohort with CKD stage II-IV. Using direct intraneural recordings and validated volume measures, we found that extracellular fluid and muscle sympathetic nerve activity increased in parallel, highlighting disrupted volume-autonomic interplay and underscoring the need to better understand neurogenic contributions to fluid dysregulation in CKD.
Dynamic and differential renal cortical cell-specific mitochondrial metabolism in response to fasting.
Feola K, Venable AH, Rasouli M … +8 more , Do J, McCoy T, Llamas CB, Straus D, Russell JC, Mishra P, Najafian B, Huen SC
Am J Physiol Renal Physiol · 2026 Feb · PMID 41428383 · Full text
The metabolic health of the kidney is directly correlated to the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel the diverse functions of the kidney is limited by the kidney's s...
The metabolic health of the kidney is directly correlated to the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel the diverse functions of the kidney is limited by the kidney's structural and functional heterogeneity, especially in key metabolic organelles such as the mitochondria. As the kidney contains many different cell types, we sought to determine the intrarenal mitochondrial heterogeneity that contributes to cell-specific metabolism. To interrogate this, we used a recently developed mitochondrial tagging technique, MITO-Tag, to isolate kidney cell-type-specific mitochondria. Here, we investigated mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag transgene was combined with , , or transgenes to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum-fed and 24-h fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities, which dynamically changed during fasting conditions. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting. This study describes the generation and application of mouse models capable of interrogating kidney tubular epithelial cell-specific mitochondrial metabolism. Applying the MITO-Tag system in the kidney, we have, for the first time, defined the mitochondrial metabolic heterogeneity of renal cortical tubular epithelium and discovered differential mitochondrial functional capacities in response to an acute metabolic stress such as fasting.
Protein phosphatase 2A subunit B55 alpha is required for angiotensin type 2 receptor elicited natriuresis.
Gildea JJ, Li J, Howell NL … +5 more , Kemp BA, Conaway MR, Brautigan DL, Carey RM, Keller SR
Am J Physiol Renal Physiol · 2026 Jan · PMID 41407311 · Full text
Angiotensin type 2 receptor (ATR) activation promotes natriuresis, thereby contributing to sodium balance and blood pressure regulation. In this study, we explored a novel intermediate in ATR signaling, protein phosphata...
Angiotensin type 2 receptor (ATR) activation promotes natriuresis, thereby contributing to sodium balance and blood pressure regulation. In this study, we explored a novel intermediate in ATR signaling, protein phosphatase 2A (PP2A) regulatory subunit B55α. Probing for PP2A subunit-ATR interactions in vivo using proximity ligation assays on kidney sections prepared from rats after renal interstitial (RI) infusion of vehicle or the ATR agonist compound 21 (C21), we observed a sixfold increase in ATR-B55α interaction in apical brush border membranes of renal proximal tubule cells (RPTCs) with C21 stimulation. In vitro binding of purified ATR and B55α supported a direct interaction between these two proteins. To test whether B55α is required for renal ATR signaling, we administered siRNA targeting B55α to rats in vivo by RI infusion, which resulted in a ∼70% decrease in B55α in proximal but not distal tubules. Remarkably, RPTC B55α knockdown abolished C21-induced natriuresis and simultaneously prevented C21-mediated ATR redistribution to apical brush border membranes and sodium transporter Na/H exchanger-3 (NHE-3) retrieval. Furthermore, B55α knockdown prevented cellular Src (c-Src) phosphorylation with C21 stimulation, increased ATR colocalization with lysosomal marker lysosomal-associated membrane protein 1 (LAMP1) by four to sixfold, and reduced ATR colocalization with early and late endosomal markers early endosome antigen 1 (EEA1) and Rab7 by 50%. In conclusion, our results show that RPTC PP2A B55α binds to activated ATR and is required for ATR signaling to natriuresis and ATR intracellular trafficking. We thus establish RPTC PP2A B55α as a key ATR signaling intermediate and potential therapeutic target to promote sodium excretion in hypertensive individuals. Protein phosphatase 2A (PP2A) B55α is required for angiotensin type 2 receptor (ATR) natriuretic signaling and ATR intracellular trafficking in renal proximal tubule cells (RPTCs). RPTC PP2A B55α is thus a key ATR signaling intermediate and potential therapeutic target to promote sodium excretion in hypertensive individuals. This study introduces knocking down B55α in vivo specifically in RPTCs using renal interstitial infusion of siRNA as a novel and unique approach to investigate physiological protein function in the kidney.
Population-level circadian rhythm of eGFR and the effect of chronodisruption.
Blázquez-Manzanera AL, Lorenzo-Lozano MC, Sánchez de Lara I … +1 more , Gómez Romero FJ
Am J Physiol Renal Physiol · 2026 Feb · PMID 41397297 · Publisher ↗
Chronic kidney disease (CKD) is one of the leading causes of global morbidity, and early diagnosis is essential to prevent complications. Estimated glomerular filtration rate (eGFR) is a key biomarker for assessing renal...
Chronic kidney disease (CKD) is one of the leading causes of global morbidity, and early diagnosis is essential to prevent complications. Estimated glomerular filtration rate (eGFR) is a key biomarker for assessing renal function. However, its value is influenced by various factors, including circadian variations. Previous studies have documented a circadian rhythm in eGFR, but population-level investigations using the cosinor method have not been conducted. We conducted a retrospective study in two hospitals in Spain (Toledo and Lorca) between 2017 and 2019. The circadian rhythm of eGFR was studied by fitting it to a cosine function, analyzing the effects of age and CKD stage. The results showed a statistically significant circadian rhythm in both populations, with the acrophase occurring at the beginning of the active phase of the day. The amplitude of the rhythm decreased in older patients (70-85 yr), whereas patients with advanced CKD had lost their circadian rhythm entirely. This study, for the first time, uses the cosinor method to demonstrate the existence of a population-level circadian rhythm of eGFR. The cosinor analysis was performed on different CKD stages and ages, revealing the existence of significant rhythms, although none at advanced ages or post-G1 CKD stage. The loss of circadian variability in advanced CKD emphasizes the importance of considering these rhythms in clinical practice to improve the diagnosis and management of kidney disease. This study, for the first time, uses the cosinor method to demonstrate the existence of a population-level circadian rhythm of estimated glomerular filtration rate, which is influenced both by age and the progression of chronic kidney disease.
Physical association of NHE3 and SGLT2 mediated by accessory proteins in the renal proximal tubule.
Polidoro JZ, de Oliveira NO, Jesus EF … +3 more , Nascimento NF, Santos CF, Girardi ACC
Am J Physiol Renal Physiol · 2026 Jan · PMID 41348647 · Publisher ↗
Proximal tubule Na/H exchanger 3 (NHE3) is tightly regulated by factors controlling extracellular volume homeostasis, blood pressure, and acid-base balance. Emerging evidence suggests that glycemic control-related factor...
Proximal tubule Na/H exchanger 3 (NHE3) is tightly regulated by factors controlling extracellular volume homeostasis, blood pressure, and acid-base balance. Emerging evidence suggests that glycemic control-related factors also influence NHE3, supporting the concept of integrated regulation of fluid and glucose handling in the proximal tubule. Accordingly, gliflozins, a class of antidiabetic drugs that inhibit the Na/glucose cotransporter sodium-glucose cotransporter 2 (SGLT2), also inhibit NHE3. We previously demonstrated that NHE3 and SGLT2, but not sodium-glucose cotransporter 1 (SGLT1), colocalize in the proximal tubule apical membrane. However, whether NHE3 and SGLT2 physically associate within a multiprotein complex has remained unclear. This study investigated whether NHE3 and SGLT2 are indirectly linked through their accessory proteins PDZ domain containing 1 (PDZK1) and MAP17. Using nondenaturing electrophoresis, we found that SGLT2 comigrates with NHE3, MAP17, and PDZK1 in a ∼480 kDa complex in rat renal cortex (∼15% of total SGLT2 in the complex population). SGLT1 and Na/K-ATPase, included as negative controls, did not comigrate with NHE3. The NHE3-PDZK1-MAP17-SGLT2 complex is present in both sexes, although distinct NHE3 and SGLT2 banding patterns may reflect sex-associated differences in complex conformation. SGLT2-NHE3 complex formation occurred irrespective of NHE3 phosphorylation at serine 552. Acute empagliflozin infusion altered the relative migration and colocalization of NHE3 with SGLT2 and MAP17 but did not disrupt overall complex integrity, supporting a conformational mechanism underlying its effects on NHE3. Together, these findings suggest that NHE3 and SGLT2 assemble into a multiprotein complex through PDZK1 and MAP17, providing mechanistic insight into the coordinated regulation of sodium, fluid, and glucose reabsorption in the proximal tubule. This study reveals that NHE3, SGLT2, and their accessory proteins, PDZK1 and MAP17, assemble into a multiprotein complex in the renal proximal tubule. The merged NHE3-SGLT2 signals show distinct intensity in females, suggesting potential sex-specific differences in complex composition or organization. Acute empagliflozin infusion modifies the colocalization patterns of NHE3 with SGLT2 and MAP17 without disrupting complex integrity, supporting a model in which SGLT2 inhibitors regulate NHE3 through conformational rearrangements within this native complex.
Chronic circadian stress impairs blood pressure and sodium homeostasis in a diet- and sex-specific manner.
Latimer MN, Rhoads MK, Reynolds LD … +1 more , Pollock DM
Am J Physiol Renal Physiol · 2026 Feb · PMID 41285411 · Publisher ↗
This study investigates the effects of environmental circadian disruption and high-fat diet (HFD) on cardiovascular and renal functions in knockout (KO) and wild-type (WT) rats. Under 12:12-h light:dark conditions, KO...
This study investigates the effects of environmental circadian disruption and high-fat diet (HFD) on cardiovascular and renal functions in knockout (KO) and wild-type (WT) rats. Under 12:12-h light:dark conditions, KO males and females on a normal fat diet (NFD) exhibit lower mean arterial pressure (MAP) compared with WT. These genotype differences were attenuated after subjecting rats to a weekly 6 h advance in the 12:12-h light:dark protocol to induce chronic circadian stress (CCS). CCS modestly elevated MAP in males, eliminating pre-existing genotypic differences, whereas in females, CCS had no significant effects on MAP and heart rate. Under HFD, genotype-based MAP differences are attenuated, and sex differences in heart rate are diminished. CCS further elevated MAP in male KO, accompanied by reduced blood pressure amplitude. Diurnal variations in sodium excretion are abolished post-CCS in both WT and KO males on HFD. In KO females, CCS combined with HFD disrupts sodium excretion rhythms, thus eliminating the protective effects seen on NFD. These findings highlight the complex interplay between circadian regulation, dietary fat, and environmental stress in modulating cardiovascular and renal physiology. This study further supports a "two-hit hypothesis," where CCS and HFD may synergistically disrupt sodium homeostasis and blood pressure circadian rhythms in both males and females. We investigate the role of , a core circadian clock gene, and diet in impairment of blood pressure and renal function during a chronic circadian stress protocol. This study finds that the endogenous molecular clock responds to circadian stress and high-fat diet in a sex-specific manner, warranting further investigation in the role of these systems in the regulation of blood pressure control and organ function.
Endothelial dysfunction accelerates AKI-to-CKD transition by promoting β-catenin activation in macrophages.
Takasu M, Kishi S, Nagasu H … +13 more , Kondo M, Wada M, Tatsugawa R, Kajimoto E, Hirano A, Iwakura T, Wada Y, Kadoya H, Kidokoro K, Iseki M, Sasaki T, Kanwar YS, Kashihara N
Am J Physiol Renal Physiol · 2026 Jan · PMID 41269672 · Publisher ↗
Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), resulting in long-term renal dysfunction. Although traditional risk factors such as hypertension, diabetes, and aging contribute to this tr...
Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), resulting in long-term renal dysfunction. Although traditional risk factors such as hypertension, diabetes, and aging contribute to this transition, endothelial dysfunction has emerged as a central mediator. In a murine model of severe ischemia-reperfusion injury (IRI), we observed persistent fibrosis with sustained activation of β-catenin signaling, especially when there is an endothelial nitric oxide synthase (eNOS) deficiency. Impaired nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling exacerbated fibrosis by failing to suppress β-catenin activity. RNA sequencing at post-IRI revealed upregulation of genes related to macrophage differentiation. Flow cytometry demonstrated a biphasic macrophage response: CD11bF4/80 (M1-like) macrophages predominated on , shifting to CD11bF4/80 (M2-like) macrophages by , and then resolving by . However, in eNOS knockout mice, M2 macrophages persisted beyond , indicating sustained fibrogenic signaling. In vitro, NO-cGMP-PKG signaling inhibited IL-4-induced M2 polarization via β-catenin degradation, linking endothelial dysfunction to prolonged M2 activation. In vivo, macrophage depletion in eNOS-deficient mice significantly reduced interstitial fibrosis and improved renal function, confirming an important pathogenic role of M2 macrophages in AKI-to-CKD progression. Furthermore, pharmacological enhancement of cGMP signaling using a phosphodiesterase-5 (PDE5) inhibitor from post-IRI ameliorated fibrosis. Together, these findings suggest that endothelial dysfunction promotes a profibrotic macrophage milieu via Wnt/β-catenin activation and highlights the therapeutic potential of targeting NO-cGMP-β-catenin signaling to prevent CKD progression following AKI. Our study provides novel insights into the mechanisms underlying the transition from acute kidney injury (AKI) to chronic kidney disease (CKD), with a focus on the role of endothelial nitric oxide synthase (eNOS). We believe our findings, particularly their potential implications for developing new therapeutic strategies to prevent CKD progression, will be of significant interest to your readership and could significantly improve patient care.
SGLT-2 inhibitors attenuate pattern-recognition molecules collectin kidney 1 and mannose-binding lectin in kidney and liver in mice with diabetes.
Jensen M, Thiel S, Hansen SWK … +3 more , Palarasah Y, Svenningsen P, Jensen BL
Am J Physiol Renal Physiol · 2026 Jan · PMID 41269668 · Publisher ↗
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors improve outcomes in diabetic nephropathy (DN) and cardiovascular disease. To elucidate the underlying protective mechanisms, we explored the hypothesis that the lectin c...
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors improve outcomes in diabetic nephropathy (DN) and cardiovascular disease. To elucidate the underlying protective mechanisms, we explored the hypothesis that the lectin complement pathway, specifically through collectin kidney 1 (CL-K1), plays a critical role in early DN. We assessed: ) CL-K1 abundance in the kidneys of diabetic mice, ) the impact of SGLT-2 inhibition on CL-K1 and complement activation, and ) the effect of CL-K1 deficiency on albuminuria and epithelial injury. Streptozotocin (STZ) was used to induce diabetes in male wild-type (WT) and CL-K1 knockout (KO) mice in three substudies. The studies evaluated time-dependent effects (14 days and 35 days), the effect of dapagliflozin, and the effect of gene deletion. Urine, plasma, and organ samples were analyzed for CL-K1 mRNA and protein levels by quantitative polymerase chain reaction (qPCR), Western blotting, and in situ hybridization. STZ-treated mice displayed elevated plasma glucose, increased kidney weight, urinary excretion of albumin, and kidney injury molecule-1. Kidney and plasma CL-K1 protein levels increased significantly and progressively in STZ-treated mice, whereas hepatic CL-K1 remained unchanged. Plasma mannose-binding lectin-C (MBL-C) and mannose-binding lectin (MBL)-associated serine proteases (MASP-1), as well as kidney CL-K1 and MBL-C mRNAs increased following STZ. Dapagliflozin reduced fasting blood glucose ( < 0.01), kidney ( < 0.05), and hepatic ( < 0.05) CL-K1 protein abundance, and plasma MBL-C levels ( < 0.01), without affecting mRNA levels. CL-K1 KO STZ mice exhibited a transient significant reduction in the albumin-creatinine ratio after 2 wk compared with WT STZ ( < 0.0001). Dapagliflozin reduced diabetes-related lectin pathway molecule levels in liver and kidney, potentially protecting the kidney through inhibition of this pathway. This study investigated how SGLT-2 inhibitors (SGLT-2is) could improve kidney outcomes in early stages of diabetic nephropathy (DN) by examining changes in and contribution of collectins. We found that levels of collectin [CL-K1 and mannose-binding lectin (MBL)] increase in the kidneys of diabetic mice as injury progresses, and SGLT-2is reduce these levels. Notably, CL-K1 deletion offered temporary protection against filtration barrier injury. These findings suggest that collectins are involved in the early stages of DN, and SGLT-2is might protect the kidneys by influencing collectin activity and reducing inflammation.
AutoGlom: software tool for segmentation and analysis of magnetic resonance images of the kidney.
Li T, Cochran A, Xu Y … +8 more , Charlton JR, Bennett KM, Timberline SM, Dailey RK, Jannath SY, Baldelomar EJ, Hoch MR, Wu T
Am J Physiol Renal Physiol · 2026 Jan · PMID 41264403 · Full text
Magnetic resonance imaging (MRI) is increasingly important in preclinical and clinical investigations of the kidney. However, there are few user-friendly, flexible, and standardized tools for evaluating MR images for qua...
Magnetic resonance imaging (MRI) is increasingly important in preclinical and clinical investigations of the kidney. However, there are few user-friendly, flexible, and standardized tools for evaluating MR images for quantitative imaging analysis. Here, we develop AutoGlom, an open-source, modular, and expandable imaging software tool that incorporates artificial intelligence (AI) for segmentation, analysis, and visualization of three-dimensional (3-D) MR images of the kidney. This initial version of AutoGlom focuses on morphological segmentation and quantification. We describe kidney segmentation from MR images, followed by the use of the graphical user interface of AutoGlom. Using AutoGlom, we measure glomerular number and volume from ex vivo cationic ferritin-enhanced MRI (CFE-MRI) in mice. We further demonstrate a 3-D-printed holder to allow for simultaneous imaging of up to 16 mouse kidneys at high resolution (50 μm) within several hours. The streamlined workflow facilitates rapid image analysis and accelerates optimization of cationic ferritin dosing and imaging parameters. These tools are a resource for the kidney community that may accelerate the identification of candidate imaging biomarkers from 3-D MRI of the kidney and have the potential to be extended to in vivo studies and other imaging modalities. We present AutoGlom, an open-source software for quantitative kidney MRI analysis. AutoGlom integrates deep learning-based glomerular segmentation, parameter tuning, and visualization within a user-friendly interface. It enables high-throughput analysis using a 3-D-printed holder for simultaneous imaging of multiple kidneys and introduces a new image quality metric, glomerular contrast, to improve reliability. AutoGlom provides standardized, reproducible workflows for glomerular quantification, bridging preclinical and translational kidney imaging and enabling future physiological discoveries.
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