American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Blood Pressure Responses to Dietary Salt in Renin-Deficient Dahl Salt-Sensitive Rats.
Xu B, Ilatovskaya DV, Levchenko V … +5 more , Zietara A, Spires D, Palygin O, Pavlov T, Staruschenko A
Am J Physiol Renal Physiol · 2026 Jul · PMID 42390335 · Publisher ↗
The renin-angiotensin-aldosterone system (RAAS) is essential in controlling fluid balance and blood pressure. In salt-sensitive (SS) hypertension, circulating RAAS is overactive, and the renin response to changes in sodi...
The renin-angiotensin-aldosterone system (RAAS) is essential in controlling fluid balance and blood pressure. In salt-sensitive (SS) hypertension, circulating RAAS is overactive, and the renin response to changes in sodium intake is bidirectionally blunted. Here, we used wild-type Dahl SS rats and renin knockout rats on the Dahl SS background (SS) to understand the role of renin in blood pressure regulation under salt-deficient (SD; 0.01% NaCl) and high-salt (HS; 4% NaCl) diets. We hypothesized that, compared to SS rats, SS rats would have lower blood pressure on the SD diet due to underdeveloped medulla and would return to normal blood pressure on the HS diet. First, we examined circulating RAAS responses after 10 days of SD and HS diets in SS rats. A 10-day SD diet robustly activated all parts of the circulating RAAS in Dahl SS rats, while a 10-day HS diet significantly decreased the aldosterone-to-Ang II ratio. Additionally, we measured mean arterial blood pressure, glomerular filtration rate, urine output, and blood and urine electrolyte levels in SS rats and SS rats (littermates) under normal salt (NS; 0.4% NaCl) and after 10 days of SD or HS diets. SD feeding significantly reduced the blood pressure, plasma Na, and Cl of SS rats. HS diet caused a rapid rise in blood pressure, with 100% mortality in SS rats. In summary, these findings demonstrate that loss of renin impairs adaptive responses to dietary salt, and proper RAAS function is vital for maintaining blood pressure in salt-sensitive hypertension.
Cytokine Profiles in Patients with Chronic Kidney Disease and Low Sexual Function.
Arriola-Montenegro J, Suvakov S, Lobo AS … +3 more , Felt M, Garovic VD, Kattah AG
Am J Physiol Renal Physiol · 2026 Jul · PMID 42390260 · Publisher ↗
Low sexual function is common in chronic kidney disease (CKD), yet the contribution of inflammatory pathways in affected women remains poorly defined. We sought to characterize cytokine profiles associated with low sexua...
Low sexual function is common in chronic kidney disease (CKD), yet the contribution of inflammatory pathways in affected women remains poorly defined. We sought to characterize cytokine profiles associated with low sexual function in women with advanced CKD. We enrolled 32 women aged 18-51 years with CKD stages 3b-5 in a cross-sectional study assessing hormonal profiles and sexual function using the Female Sexual Function Index (FSFI); low sexual function was defined as FSFI < 26.55. Plasma samples were analyzed using a 48-plex cytokine assay. Cytokine concentrations were compared using the Wilcoxon two-sample test, with false discovery rate control (FDR < 0.05) via the Benjamin-Hochberg procedure. Principal component analysis (PCA) was used to evaluate cytokine patterns associated with low sexual function. Thirty participants completed the FSFI; 22 (73%) met criteria for low sexual function. Of 48 cytokines examined, soluble CD40 ligand (sCD40L) was the only marker that remained significant after FDR correction, with lower levels observed in women with low sexual function (median 520.9 vs. 1140 pg/mL; p = 0.0004; FDR = 0.02). Each 100 pg/mL increase in sCD40L was associated with a 34% reduction in odds of having low sexual function after adjusting for age and estimated glomerular filtration rate (adjusted OR 0.66 (95% CI 0.49 - 0.90)). PCA revealed that principal component 1 explained 37.4% of the variance and higher levels were associated with a higher odds of low sexual function (OR 1.42 (95% CI 1.03-1.96)). Low sexual function was highly prevalent and associated with differences in inflammatory and immune signaling, suggesting immune-vascular pathways may influence female sexual health in CKD.
Renovascular disease induces functionally relevant, locus-specific alterations to DNA methylation and hydroxymethylation in swine scattered tubular-like cells.
Iyer VC, Shivam K, Kazeminia S … +8 more , Zhu XY, Tang H, Xue A, Herrmann SM, Chade AR, Irazabal MV, Lerman LO, Eirin A
Am J Physiol Renal Physiol · 2026 Jul · PMID 42390182 · Publisher ↗
Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. STCs may be damaged and rendered ineffective by renovascular disease (RVD), but the underlying mechanis...
Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. STCs may be damaged and rendered ineffective by renovascular disease (RVD), but the underlying mechanisms remain unknown. We hypothesized that RVD induces changes in methylated (5mC) and hydroxymethylated (5hmC) DNA and modulates the transcriptomic profile and functional properties of swine STCs. CD24+/CD133+ STCs were harvested from pig kidneys after 10 weeks of RVD or sham (n=6 each) and their 5mC and 5hmC profiles of individual peaks were examined by immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively, n=3 each). Integrated (MeDIP/hMeDIPseq/mRNA-seq) analysis was performed followed by functional analysis of overlapping differentially expressed (DE) genes. STC-protective effects were assessed in vitro before and after epigenetic (Bobcat339) modulation. MeDIP-seq analysis identified 1,362 hyper-methylated and 1,432 hypo-methylated peaks in RVD-STCs compared to Normal-STCs, which correlated with 80 upregulated and 55 downregulated genes in RVD-STCs. hMeDIP-seq revealed 1,447 hyper-hydroxymethylated and 765 hypo-hydroxymethylated peaks in RVD-STCs versus Normal-STCs, which correlated with 80 genes upregulated and 53 downregulated in RVD-STCs. Overlapping upregulated genes were mainly implicated in the regulation of oxidative phosphorylation, apoptosis, and lipid metabolism (e.g., STAT6), whereas overlapping downregulated genes were mainly involved in cell proliferation. Importantly, RVD increased STAT6 protein expression and impaired the proliferative capacity of STCs, which were partially reversed by treatment with Bobcat339, which also enhanced the ability of RVD-STCs to promote the viability of injured tubular epithelial cells. Renal ischemia induces locus-specific epigenetic alterations, associated with transcriptomic changes and impaired reparative function of swine STCs. These observations may contribute to develop novel approaches to preserve the reparative capacity of STCs in individuals with RVD.
Nitrite Protects Against Cardiac Surgery-Associated Acute Kidney Injury via Inflammation Suppression: Insights from a Rat Cardiopulmonary Bypass Model.
Ohno S, Yoshikawa Y, Maeda M … +7 more , Hirahata T, Kii N, Sawashita Y, Osanai M, Kanda M, Hirata N, Yamakage M
Am J Physiol Renal Physiol · 2026 Jul · PMID 42390113 · Publisher ↗
Cardiac surgery-associated acute kidney injury (CS-AKI) is reported in 20-30% of patients undergoing cardiac surgery, leading to poor outcomes and increased healthcare costs. Because the pathophysiology of CS-AKI remains...
Cardiac surgery-associated acute kidney injury (CS-AKI) is reported in 20-30% of patients undergoing cardiac surgery, leading to poor outcomes and increased healthcare costs. Because the pathophysiology of CS-AKI remains incompletely understood, no effective preventive strategies exist. Nitrite, a nitric oxide donor under hypoxic conditions, has been shown to exert organ-protective effects in various preclinical models. However, its protective effects against CS-AKI remain unexplored. This study aimed to generate a rat cardiopulmonary bypass (CPB) model to induce CS-AKI, identify the key molecular pathways involved in its pathophysiology, and evaluate the potential renoprotective effects of nitrite. A rat CPB model was established, and CS-AKI was confirmed through molecular and histological analyses. RNA-sequencing (RNA-seq) was performed to identify differentially expressed genes and enriched pathways. Nitrite (2 mg/kg) was administered before CPB, and its effects on kidney injury markers and inflammation-related pathways were evaluated. CS-AKI was successfully induced in our rat CPB model, as evidenced by increased KIM-1 and NGAL expression and renal histological damage. RNA¬-seq revealed activation of inflammation-related pathways, including the TNF and NFκB signaling pathways. Nitrite administration significantly reduced KIM-1 and NGAL expression and suppressed pathways associated with CS-AKI development. This study underscores the role of inflammation in the pathophysiology of CS-AKI and demonstrates that nitrite attenuates early tubular injury markers and inflammation-related pathways. These findings support further investigation of nitrite as a strategy to mitigate tubular injury during cardiac surgery.
Etanercept attenuates TNFα-mediated kidney injury in a rat model of brain death kidney donation.
Pinto Coelho T, Abdelmalki J, Navez M … +4 more , Vandermeulen M, Erpicum P, Detry O, Jouret F
Am J Physiol Renal Physiol · 2026 Jun · PMID 42363823 · Publisher ↗
Brain death (BD) induces a robust inflammatory response that impairs kidney quality before transplantation. Given that TNFα is a central upstream mediator of BD-related injury, we investigated whether selective TNFα inhi...
Brain death (BD) induces a robust inflammatory response that impairs kidney quality before transplantation. Given that TNFα is a central upstream mediator of BD-related injury, we investigated whether selective TNFα inhibition using etanercept could mitigate renal damage in a rat model of BD. BD was maintained for 6 hours in anesthetized rats (n=6 controls; n=12 etanercept-treated; balanced for sex), after which animals were randomized to receive either etanercept (ETNCPT) or vehicle (CTL). We evaluated serum biomarkers, histological kidney injury, immune cell infiltration, and whole-kidney transcriptomic profiles. Etanercept significantly reduced circulating TNFα levels (15.25[12.30-21.05] vs. 34.23[26.03-50.19] pg/mL; p<0.001), while other cytokines remained unchanged. Kidney function parameters (serum creatinine, BUN), electrolytes, and hemodynamics were similar accross groups. In contrast, etanercept markedly attenuated renal injury, reducing acute tubular necrosis (30.0 [15.0-35.0]% vs. 42.5 [40.0-51.3]%; p<0.001), CD11b⁺ myeloid infiltration (0.13 [0.11-0.15]% vs. 0.21 [0.19-0.27]%; p<0.001), tubular KIM-1 expression (0.04 [0.01-0.08]% vs. 0.17 [0.13-0.18]%; p<0.001), and apoptosis (-69%; p=0.036). Transcriptomic analysis identified 281 differentially expressed genes after TNFα blockade, with strong inhibition of inflammatory and apoptotic pathways including TNF signaling, TNFR1/TNFR2 activation, death receptor signaling, and cytokine storm signaling. Predicted downstream effects included reduced kidney cell death and inflammation. Sex-stratified analyses showed similar directional effects in males and females. In summary, early TNFα blockade after BD selectively neutralizes TNFα, limits immune recruitment, and suppresses injury and inflammatory signaling at cellular and transcriptomic levels. Targeting TNFα during kidney donor management may offer a promising strategy to improve kidney quality before transplantation.
Phosphorylation of aquaporin-2 at serine 269 in urinary extracellular vesicles reflects renal vasopressin activity in rats.
Higashijima Y, Moriwaki M, Kawaguchi T … +5 more , Yokote T, Imanuelle N, Matsuzaki T, Sonoda H, Ikeda M
Am J Physiol Renal Physiol · 2026 Jun · PMID 42345393 · Publisher ↗
Through activation of the arginine vasopressin (AVP) receptor 2 in the renal collecting duct, phosphorylation of the C-terminus of aquaporin-2 (AQP2) triggers AQP2 translocation to the apical membrane, thereby enhancing...
Through activation of the arginine vasopressin (AVP) receptor 2 in the renal collecting duct, phosphorylation of the C-terminus of aquaporin-2 (AQP2) triggers AQP2 translocation to the apical membrane, thereby enhancing water reabsorption. AQP2 is excreted into urine via urinary extracellular vesicles (uEVs). Recently, phosphorylated S256 and S269 AQP2 (pS256- and pS269-AQP2), both of which are well-characterized phosphorylated AQP2, have been detected in murine uEVs. However, their biological significance in uEVs remains poorly understood. Here, we employed validated antibodies against pS256- and pS269-AQP2 to investigate the effect of AVP on the secretion of these forms into uEVs. In a rat hydration model, uEV pS269-AQP2 showed the most pronounced increase compared with total AQP2 (phosphorylated + non-phosphorylated forms) and pS256-AQP2 after single-dose treatment with a synthetic AVP analogue, dDAVP. A similar response pattern was observed in a long-term dDAVP-treatment model. Unlike total AQP2 and pS256-AQP2, pS269-AQP2 was localized predominantly at the apical membrane of renal collecting duct cells, regardless of dDAVP treatment or hydration status. Furthermore, in a dehydration/hydration model, uEV pS269-AQP2 showed a close association with urinary osmolality and electrolyte concentrations. Although uEV pS256-AQP2 was also associated with these urinary indices, the relationship was more robust for uEV pS269-AQP2. By contrast, uEV total AQP2 did not correlate significantly with urinary osmolality or electrolyte concentrations. These findings suggest that secretion of pS269-AQP2 in uEVs accurately reflects renal AVP activity. Given the technical challenges in measuring blood AVP, pS269-AQP2 in uEVs may hold promise as a non-invasive biomarker of renal AVP activity.
Influence of serum chloride concentrations on the renin-angiotensin-aldosterone system in dogs with congestive heart failure.
Adin D, Qu Y, Domenig O … +1 more , Harris A
Am J Physiol Renal Physiol · 2026 Jun · PMID 42324236 · Publisher ↗
Chloride is a key determinant of macula densa signaling and renin release, but its relationship with systemic renin-angiotensin-aldosterone system (RAAS) activity in naturally occurring heart failure is incompletely defi...
Chloride is a key determinant of macula densa signaling and renin release, but its relationship with systemic renin-angiotensin-aldosterone system (RAAS) activity in naturally occurring heart failure is incompletely defined. We evaluated associations between serum chloride concentration and circulating RAAS metabolites in 147 dogs (20 healthy, 39 preclinical heart disease, 88 congestive heart failure [CHF]). Circulating angiotensin metabolites, aldosterone, and ACE and ACE2 activity were quantified by liquid chromatography-mass spectrometry. Associations between serum chloride and RAAS components were assessed using HC3 robust multivariable linear regression adjusted for sex, ACE inhibitor use, and serum bicarbonate. Dogs with CHF had higher circulating RAAS metabolites than healthy and preclinical dogs. Serum chloride was inversely correlated with multiple RAAS metabolites, including Ang I (rₛ = -0.515) and Ang 1-7 (rₛ = -0.546; both P < 0.0001). Lower serum chloride was independently associated with higher concentrations of angiotensin peptides (Ang I, II, III, IV, and Ang 1-7) and aldosterone, with each 5 mmol/L decrease corresponding to 32-45% increases in angiotensin metabolites and a 39% increase in aldosterone (all adjusted P ≤ 0.02). Hypochloremia (<100 mEq/L) identified a distinct RAAS phenotype characterized by higher downstream angiotensin metabolites, including Ang II, III, and IV (all adjusted P ≤ 0.03). Chloride was not associated with ACE or ACE2 activity. Serum chloride is independently associated with systemic RAAS activation in dogs with heart disease, supporting an association between lower serum chloride concentrations and enhanced upstream of RAAS pathway flux.
A New Brake on Podocyte Injury: ATOH8 Meets TGF-β.
Shankland SJ, Wessely O
Am J Physiol Renal Physiol · 2026 Jun · PMID 42315098 · Publisher ↗
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A-Intercalated Cell Dysfunction Disrupts Renal Epithelial-Immune Balance and Impairs Host Defense During UTI.
Chelangarimiyandoab F, MacNaughton K, Essuman G … +1 more , Cordat E
Am J Physiol Renal Physiol · 2026 Jun · PMID 42294520 · Publisher ↗
Intercalated cells (ICs) of the renal collecting duct are traditionally recognized for their role in acid-base homeostasis, but growing evidence suggests they also participate in innate immune defense. Although ICs have...
Intercalated cells (ICs) of the renal collecting duct are traditionally recognized for their role in acid-base homeostasis, but growing evidence suggests they also participate in innate immune defense. Although ICs have been implicated in renal antimicrobial function, their specific role in coordinating immune responses during urinary tract infection (UTI) remains unclear. Using Ae1 R607H knock-in mice, a distal renal tubular acidosis (dRTA) model with A-intercalated cell (A-IC) dysfunction, we examined the renal response to uropathogenic (UPEC). Mice with A-IC dysfunction exhibited higher bacterial loads 24 h post-infection and increased renal expression of antimicrobial peptides lipocalin-2 (), galectin-3 (), and cathelicidin-related antimicrobial peptide (). Pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) were elevated at both transcript and protein levels, whereas tumor necrosis factor-α (TNF-α) increased only at the protein level. Interleukin-10 (IL-10) showed a modest rise in mRNA. Chemokines C-X-C motif chemokine ligand 2 () and C-C motif chemokine ligand 2 () were also upregulated, accompanied by excessive neutrophil infiltration and a marked shift in renal myeloid-cell composition. A-IC dysfunction therefore correlates with higher bacterial load, exaggerated inflammation and impaired immune resolution. These findings identify A-ICs as essential epithelial immunomodulators that integrate antimicrobial defense, cytokine regulation, and immune-cell recruitment during UTI.
Heat Shock Protein 72 is a Druggable Target During Cold Storage to Improve Graft Outcome After Kidney Transplantation.
Lee SO, Sharma A, Bhattarai D … +7 more , Venugopal G, Jun SR, Gokden N, Arthur JM, MacMillan-Crow LA, Rusch NJ, Parajuli N
Am J Physiol Renal Physiol · 2026 Jun · PMID 42284097 · Publisher ↗
Prolonged cold storage (CS) of donor kidneys results in poor outcomes after transplantation. We reported earlier that cold storage (CS) of rat kidneys for 18 hours (h) followed by transplantation (CS+Tx) reduces proteaso...
Prolonged cold storage (CS) of donor kidneys results in poor outcomes after transplantation. We reported earlier that cold storage (CS) of rat kidneys for 18 hours (h) followed by transplantation (CS+Tx) reduces proteasome function, disrupts protein homeostasis, and compromises graft function. The goal of the present study was to define the contribution of specific heat shock proteins (Hsp) to CS-induced disruption of renal graft function and determine the benefit conferred by their pharmacological inhibition. We subjected kidneys isolated from donor Lewis rats to 18-h CS with or without pharmacological inhibition of heat-shock protein 72 (Hsp72), a stress-inducible member of the Hsp70 family. Subsequently, the donor kidneys were transplanted into Lewis rats (CS+Tx). Hsp72 was upregulated in kidney grafts after CS+Tx and this finding was coupled to a reciprocal loss of cognate Hsc70 and profound tubular injury. Knockdown of Hsc70 in renal cells increased Hsp72, compromised proteasome function, and increased mitochondrial oxidative stress. The addition of HS-72, a Hsp72-specific inhibitor, to the CS solution restored proteasome function and improved renal injury/function after transplantation. Our study shows that CS+Tx dysregulates heat shock proteins in the kidney and targeting a single disrupted protein, Hsp72, can improve graft function.
Cell-specific Y-box binding protein-1 drives liver-kidney injury in cholestasis.
Liu X, Hermert D, Chen Y … +12 more , Martin IV, Gao Y, Rawinski R, Leitz A, Wang J, Djudjaj S, Reiss LK, Kramann R, Floege J, Weiskirchen R, Ostendorf T, Raffetseder U
Am J Physiol Renal Physiol · 2026 Jun · PMID 42284095 · Publisher ↗
Acute kidney injury is a frequent, life-threatening complication of liver disease. The stress-responsive DNA- and RNA-binding protein Y-box-binding protein 1 (YB-1) regulates gene expression and modulates liver-kidney cr...
Acute kidney injury is a frequent, life-threatening complication of liver disease. The stress-responsive DNA- and RNA-binding protein Y-box-binding protein 1 (YB-1) regulates gene expression and modulates liver-kidney crosstalk, with partial systemic YB-1 deficiency protecting the liver but worsening kidney injury in a murine bile duct ligation (BDL) model. To further define cell-specific roles of YB-1, its expression was selectively reduced in kidney and immune cells, and the effects on primary liver and secondary kidney injury were evaluated. Conditional knockout mice targeting tubular () and myeloid () cells were used to study YB-1 function during BDL-induced cholestasis and kidney damage. Organ injury and fibrosis were evaluated by histology, gene expression, and serum markers. Tubular YB-1 deficiency was associated with reduced kidney injury and fibrosis. This was accompanied by a decreased expression of the bile acid uptake transporter ASBT and an increased expression of the efflux transporter OSTβ. These changes are consistent with a coordinated detoxification response limiting intracellular bile acid accumulation. However, this deficiency aggravated liver damage after BDL. In contrast, myeloid YB-1 deficiency reduced serum markers of liver injury but worsened renal inflammation and injury, mirroring findings in whole-body haploinsufficient mice. These findings identify YB-1 as a crucial regulator of organ-specific responses in cholestatic liver disease, with opposing, cell type-dependent effects on liver and kidney injury, highlighting its central role in inter-organ communication.
Disruption of Polycystin-1 Cleavage Impairs Mitochondrial Bioenergetics and Calcium Uptake in a Substrate-Dependent Manner.
Amaral AG, Serna JDC, Caldeira da Silva CC … +3 more , Costa ES, Onuchic LF, Kowaltowski AJ
Am J Physiol Renal Physiol · 2026 Jun · PMID 42275149 · Publisher ↗
Metabolic and mitochondrial alterations are central in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (ADPKD), since therapies targeting these alterations slow kidney disease progression in orthologous...
Metabolic and mitochondrial alterations are central in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (ADPKD), since therapies targeting these alterations slow kidney disease progression in orthologous animal models. To investigate metabolic and mitochondrial defects in an animal model orthologous to ADPKD, we used male mice homozygous for a point variant in the GPS cleavage site of the polycystin-1 () and evaluated oxygen consumption, Ca uptake, and redox state in the mitochondrial fraction of kidneys and wild-type controls (WT). Our findings revealed mitochondrial heterogeneity in kidneys, with regions of preserved morphology alongside areas displaying swollen and disorganized mitochondria. Notably, preserved mitochondria were smaller, with either unchanged mitochondrial mass markers (TFAM, CYTC, mDNA/nDNA) or increased TOM20 levels compared to WT. Mitochondria isolated from kidneys showed reduction in oxygen consumption rates and calcium retention capacity in the presence of NADH-generating substrates, but not in the presence of succinate. Consistently, levels of specific proteins of complex I, III, and V were decreased, but not of complex II. Proteins involved in calcium homeostasis (VDAC1, MCU, MICU1, MICU2, and NCLX) were decreased in kidneys. No change in HRP-HO-mediated Amplex-red oxidation was observed in diseased mitochondria, and mitochondrial 4-HNE levels were unchanged, although increased in whole-kidney extracts. Together our results showed that cleaved PC1 plays a critical role in maintaining mitochondrial mass, integrity, and function. Given the orthologous nature of our animal model, the observed alterations may be applicable to human ADPKD.
Proteinuria Remission Profiles in Obesity-Related Kidney Disease after Bariatric Surgery.
Pereira PR, Braga P, Pereira J … +5 more , Pereira SS, Nora M, Guimarães M, Rodrigues A, Monteiro MP
Am J Physiol Renal Physiol · 2026 Jun · PMID 42262750 · Publisher ↗
Bariatric surgery improves obesity-related kidney dysfunction (ORKD), yet the determinants of full remission or persistent renal damage remain poorly understood. We evaluated factors associated with proteinuria remission...
Bariatric surgery improves obesity-related kidney dysfunction (ORKD), yet the determinants of full remission or persistent renal damage remain poorly understood. We evaluated factors associated with proteinuria remission after bariatric surgery in patients with ORKD. From a prospective cohort with 242 patients with obesity, a subgroup of 39 patients with obesity and proteinuria was followed for 21.3 months after bariatric surgery. Pre- and post-operative assessments included anthropometric, metabolic, and renal parameters. Bariatric surgery led to a total weight loss of 38.5±11.8%. Proteinuria and albuminuria declined significantly (ΔProteinuria: -43.0%; ΔAlbuminuria: -14.3%). Higher pre-operative percentage of albuminuria was associated with greater post-operative albuminuria reduction (HR: 1.979; 95% CI: 0.686 to 3.272; p<0.05). Persistent proteinuria was observed in 25.6% of patients despite substantial weight loss and showed sex-related differences, as these patients were predominantly male (60.0% vs. 20.7%, p<0.05). Persistent damage was also associated with lower serum creatinine (0.62±0.07 mg/dL vs. 0.72±0.13 mg/dL, p 0.05), and higher eGFR (117.4±8.8 vs. 104.8±12.4 mL/min/1.73m², p<0.05). In conclusion, patients with ORKD experienced marked reductions in proteinuria and albuminuria after bariatric surgery. However, a subset of patients-primarily males with higher baseline eGFR-had persistent proteinuria despite effective weight loss, suggesting the presence of potentially irreversible kidney damage.
Mechanism of impaired potassium transport in pseudohypoaldosteronism (type II).
Lessa LMA, Wan L, Yan Q … +4 more , Shen E, Malnic G, Giebisch G, Wang T
Am J Physiol Renal Physiol · 2026 Jul · PMID 42258358 · Publisher ↗
Pseudohypoaldosteronism type II (PHAII), also known as Gordon syndrome, is an autosomal-dominant disorder caused by mutations in (WNK4) and is characterized by increased renal sodium chloride (NaCl) reabsorption and imp...
Pseudohypoaldosteronism type II (PHAII), also known as Gordon syndrome, is an autosomal-dominant disorder caused by mutations in (WNK4) and is characterized by increased renal sodium chloride (NaCl) reabsorption and impaired potassium (K) secretion. We examined the relative contributions of renal outer medullary K (ROMK) channels and large-conductance Ca-activated K (BK; Maxi-K) channels to distal K secretion in wild-type (TgWnk4) and PHAII mutant (TgWnk4) mice. Renal clearance and stationery microperfusion techniques were used to assess urinary Na and K excretion and K secretion in the late distal tubule. Potassium secretion () and the half-time to reach steady-state luminal K concentration () were measured under control-K (CK) and high-K (HK) dietary conditions. Quantitative PCR revealed reduced ROMK expression in TgWnk4 mice compared with wild-type mice. Micropuncture studies showed significantly reduced K secretion in the late distal tubule under CK conditions in TgWnk4 mice. Iberiotoxin had no effect on or in either genotype under CK conditions. In contrast, HK feeding increased distal K secretion in both genotypes, and this increase was completely abolished by iberiotoxin. These findings indicate that impaired K secretion in TgWnk4 mice is due to reduced ROMK-mediated transport and is not compensated by Maxi-K channels under normal K intake. The TgWnk4 mutation does not impair HK-stimulated Maxi-K channel-mediated K secretion in the distal nephron. Our findings demonstrate that PHAII-associated WNK4 mutations impair ROMK-dependent distal K secretion while preserving high-K-stimulated Maxi-K channel function, thereby revealing distinct contributions of these channels to renal K homeostasis.
Sex differences in the renal T cell profile in DOCA-salt hypertension are independent of MR activation and increases in blood pressure.
Mohamed R, Belanger KM, Moronge D … +2 more , Elmarakby AA, Sullivan JC
Am J Physiol Renal Physiol · 2026 Jul · PMID 42258340 · Publisher ↗
We previously reported that T cells contribute to sex differences in blood pressure (BP) in deoxycorticosterone acetate (DOCA)-salt hypertension, yet the mechanism(s) modulating T-cell activation are still being investig...
We previously reported that T cells contribute to sex differences in blood pressure (BP) in deoxycorticosterone acetate (DOCA)-salt hypertension, yet the mechanism(s) modulating T-cell activation are still being investigated. The goal of the current study was to determine the relative contribution of mineralocorticoid receptor (MR) activation versus increases in BP to changes in the renal T cell profile in male and female DOCA-salt rats. Ten-week-old uninephrectomized male and female Sprague Dawley rats were implanted with a subcutaneous 21-day slow-release DOCA pellet (200 mg). To assess the relative contribution of MR activation versus the development of hypertension, subsets of male and female DOCA rats were randomized to ) saline vehicle (0.9% NaCl), ) saline plus specific MR antagonist eplerenone (100 mg/kg/day), ) saline plus BP-lowering drugs hydrochlorothiazide and reserpine (HCTZ/Res) throughout 3-wk DOCA treatment. BP was measured via radiotelemetry. Kidneys were harvested and processed for flow cytometry, biochemical, and histological analysis. Males exhibited greater increases in BP with DOCA than females. Eplerenone treatment attenuated DOCA-salt hypertension. Eplerenone significantly decreased proinflammatory Th17 cells and increased anti-inflammatory Tregs in both sexes, however sex differences in the renal T cell profile were largely maintained. To separate the effects of lowering BP from blocking MR inhibition, HCTZ/Res was used to block DOCA-salt induced hypertension. HCTZ/Res also attenuated the proinflammatory renal T cells in DOCA-salt hypertension, and sex differences in renal T cells were largely maintained. These data suggest that neither MR activation nor elevation in BP mediates the sex differences in the renal T cell profile in DOCA-salt rats. Both MR blockade and preventing the development of hypertension with HCTZ/Resp reduced proinflammatory T cells and increased anti-inflammatory cells in male and female DOCA-salt hypertensive rats. However, sex differences in the renal T cell profiles persisted.
Epigenetic regulation of nephrogenesis: from Waddington's landscape to adult disease.
Tortelote GG, El-Dahr SS
Am J Physiol Renal Physiol · 2026 Jul · PMID 42241656 · Publisher ↗
The establishment of lifelong nephron endowment depends on the tightly coordinated regulation of nephron progenitor cell (NPC) self-renewal, lineage specification, and differentiation during kidney development. Conrad H....
The establishment of lifelong nephron endowment depends on the tightly coordinated regulation of nephron progenitor cell (NPC) self-renewal, lineage specification, and differentiation during kidney development. Conrad H. Waddington's developmental landscape provides a powerful conceptual framework for understanding how NPCs navigate sequential fate decisions toward mature renal epithelial identities. Within this paradigm, the topology of the landscape is actively shaped by epigenetic mechanisms, including DNA methylation, histone posttranslational modifications, noncoding RNA-mediated gene regulation, and higher-order chromatin organization, which collectively control the timing, location, duration, and strength of gene expression programs that direct nephrogenesis. Under normal conditions, these epigenetic programs preserve progenitor competence while progressively stabilizing lineage commitment and nephron patterning. When disrupted, however, they impair progenitor plasticity, accelerate NPC pool depletion, and ultimately reduce nephron number. Such maladaptive epigenetic reprogramming establishes a mechanistic link between adverse intrauterine environments and lifelong susceptibility to hypertension and chronic kidney disease. In this review, we revisit Waddington's landscape in the context of renal development and integrate emerging insights from developmental biology, cell metabolism, and epigenomics to examine how early-life environmental perturbations durably reshape the nephrogenic program and increase the risk of adult-onset kidney disease.
Urine-derived stem cell extracellular vesicles promote recovery from acute kidney injury in mice and human kidney organoids.
Qian ES, Bejoy J, Welch RC … +6 more , Farry JM, Hartert J, Cartailler JP, Gibson-Corley KN, Wilson MH, Woodard LE
Am J Physiol Renal Physiol · 2026 Jun · PMID 42222936 · Publisher ↗
Extracellular vesicles (EVs) contain RNA, protein, lipids, and other molecules from their parental cell type, which led to the hypothesis that urine-derived stem cell EVs (USC-EVs) could have potent regenerative effects...
Extracellular vesicles (EVs) contain RNA, protein, lipids, and other molecules from their parental cell type, which led to the hypothesis that urine-derived stem cell EVs (USC-EVs) could have potent regenerative effects in the setting of acute kidney injury (AKI). We tested this hypothesis in two different AKI models and an AKI model. To test USC-EVs ability to recover human kidney cells from nephrotoxicity, HK-2 human proximal tubular epithelial cell line and human kidney organoids derived from induced pluripotent stem cells were treated with 5 μM cisplatin for 48 h followed by 10 μg USC-EVs for 48 h. We next also tested USC-EVs in the unilateral nephrectomy followed by ischemia reperfusion model (UNIRI) AKI model to explore systemic effects in animals. USC-EV treatment of human kidney cells resulted in increased cellular proliferation (p ≤ 0.0001), decreased cytotoxicity (p < 0.0001), and lowered oxidative stress (p ≤ 0.01) as compared to cisplatin alone groups. In mouse models, we found improved pathology as well as reduced kidney injury marker KIM-1 expression in the USC-EV treated group as compared to the UNIRI alone group. Analysis of USC-EV miRNA-targeting pathways associated with epithelial cell proliferation, migration, and positive regulation of MAPK signaling pathway. As predicted by this analysis, we found increased phosphorylation of the MAPK downstream target ERK1/2 in USC-EV-treated HK-2 cells. This study suggests that much of the reported benefit of USCs is due to their EVs and supports further development of USC-EVs as a potential next-generation therapeutic for AKI.
Pharmacologic disruption of HuR-RNA interactions prevents maladaptive tubular repair and AKI-to-CKD progression.
Wang Z, Liu S, Zhuang L … +5 more , Qiu Y, Aube J, Wu X, Xu L, Huang Y
Am J Physiol Renal Physiol · 2026 Jul · PMID 42213719 · Full text
Acute kidney injury (AKI) predisposes survivors to chronic kidney disease (CKD), yet the postinjury mechanisms that drive maladaptive tubular repair are incompletely defined. The RNA-binding protein HuR (ELAVL1) stabiliz...
Acute kidney injury (AKI) predisposes survivors to chronic kidney disease (CKD), yet the postinjury mechanisms that drive maladaptive tubular repair are incompletely defined. The RNA-binding protein HuR (ELAVL1) stabilizes inflammatory and profibrotic transcripts but its role in AKI-to-CKD progression is unclear. We used aristolochic acid nephropathy (AAN) to test whether disrupting HuR-RNA interactions with the small molecule KH3 mitigates AKI-to-CKD transition. Single AA exposure produced dose-dependent AKI within 72 h, whereas repeated AA induced a sustained CKD phenotype with tubulointerstitial fibrosis. AA increased HuR expression and cytoplasmic localization in injured tubular epithelial cells and circulating exosomes. KH3 administration reduced blood urea nitrogen (BUN) and creatinine, attenuated albuminuria, preserved tubular histology, and suppressed profibrotic and proinflammatory signaling in both acute and chronic AA models. Mechanistically, KH3 diminished AA-induced activation of NF-κBp65 and AKT, reduced markers of DNA damage, apoptosis, and senescence (such as γ-H2AX, cleaved PARP1/caspase-3, p21, and p16-INK4a), and normalized ferroptosis-associated proteins in AA-treated human proximal tubular cells. These results identify HuR as a central posttranscriptional regulator of maladaptive tubular repair and provide proof-of-concept that pharmacologic targeting of HuR-RNA interactions can prevent progression from AKI to CKD. This study identifies the RNA-binding protein HuR as a key regulator of maladaptive tubular repair during AKI-to-CKD transition. Pharmacologic disruption of HuR-RNA interactions with the small molecule inhibitor KH3 attenuated tubular injury, inflammation, senescence, and fibrosis in aristolochic acid-induced nephropathy. These findings provide mechanistic insight into posttranscriptional control of kidney injury and establish HuR inhibition as a promising therapeutic strategy to prevent CKD progression following AKI.
Transcriptomics of S3 segment in mice: response to type 1 diabetes, SGLT1/2 inhibition, or GLP1 receptor agonism.
Kim YC, Meng C, Kanoo S … +3 more , Thomson S, Karihaloo A, Vallon V
Am J Physiol Renal Physiol · 2026 Jul · PMID 42213650 · Publisher ↗
Inhibitors of SGLT2 (SGLT2is) and diabetes enhance glucose delivery and reabsorption in late proximal tubule S3 segments. Molecular consequences remain poorly understood. Here, we determined transcriptomic changes in S3...
Inhibitors of SGLT2 (SGLT2is) and diabetes enhance glucose delivery and reabsorption in late proximal tubule S3 segments. Molecular consequences remain poorly understood. Here, we determined transcriptomic changes in S3 segments of male adult DBA wild-type (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) given vehicle or SGLT2i dapagliflozin for 2 wk, and in Akita mice receiving glucagon-like peptide-1 receptor (GLP1R) agonist (GLP1RA) semaglutide. RNA sequencing was performed in S3 segments isolated by immunostaining-guided laser-capture-microdissection in deep cortex/outer medulla. Among 19,068 detected annotated genes, 838 genes were differentially expressed by SGLT2is in WT (differentially expressed genes; DEGs; < 0.05) and 1,410 genes in Akita vs. WT. Approximately 34% of SGLT2i-sensitive genes changed in the same direction in Akita. Both maneuvers upregulated pathways of cellular proliferation (confirmed by phospho-Ser10 Histone H3 staining) and cellular response to stress, while downregulating pathways of immune/inflammatory response, cytokine production/receptor signaling, and cell adhesion/migration. Both maneuvers also induced unique responses. Unique pathway responses to SGLT2is in WT included an increase in DNA dealkylation/demethylation and lysosomal acidification, and reduced valine biosynthesis. Differences in SGLT1-dependency of responses to Akita vs. SGLT2is in WT suggested different initiating mechanisms. In Akita, SGLT2is, Sglt1-KO, and GLP1R agonism restored 12%, 18%, and 25% of DEGs, respectively; combined SGLT2i/Sglt1-KO was not synergistic. Akita downregulated whole kidney SGLT1 membrane expression, potentially to limit glucose-induced stress. GLP1RA reduced/restored cellular stress response and proliferation in Akita in S3 segments, associated with enhanced/restored kidney membrane expression of SGLT1. Finally, Akita-sensitive genes unresponsive to any of the three maneuvers were identified that may indicate new therapeutic avenues. Both SGLT2 inhibition and diabetes increase glucose delivery to late proximal tubule S3 segments. Using transcriptomic mapping in mice, we found that both conditions induce cellular proliferation and stress responses while suppressing inflammatory pathways, but also trigger unique responses. Responses differed in their SGLT1-dependency, suggesting different initiating mechanisms. Diabetes suppressed SGLT1 expression, potentially to limit glucose-induced stress. Glucagon-like peptide-1 receptor (GLP1R) agonism reversed many diabetic transcriptomic changes in S3 segments, including stress response, associated with restored SGLT1 expression.
A novel two-hit murine model of viral-primed sepsis-associated acute kidney injury.
Odum JD, Vollmer GA, Akhter J … +5 more , Laprocina K, Richter RP, Richter JR, Agarwal A, Bolisetty S
Am J Physiol Renal Physiol · 2026 Jun · PMID 42160475 · Publisher ↗
Viral priming refers to the host's recognition of viral components, triggering an antiviral response, and upregulating pathogen recognition receptors. When followed closely by bacterial infection, this immune activation...
Viral priming refers to the host's recognition of viral components, triggering an antiviral response, and upregulating pathogen recognition receptors. When followed closely by bacterial infection, this immune activation can provoke a hyperinflammatory response, increasing the risk for secondary hemophagocytic lymphohistiocytosis (sHLH), multiorgan failure, and death. We developed a novel murine two-hit model of viral-primed sepsis-associated acute kidney injury using polyinosinic-polycytidylic acid [poly(I:C)] for viral mimicry and lipopolysaccharide (LPS) for bacterial stimulation. Male 8-wk-old C57BL/6J mice were primed with poly(I:C) [2.5 mg/kg, intraperitoneal (ip) injection] at 24 h before low-dose LPS (0.5 mg/kg, ip) (time = 0 h) and compared with vehicle-treated controls for up to 48 h. Poly(I:C) + LPS mice exhibited a significant reduction in glomerular filtration rate at 4 h post-LPS and elevated serum creatinine and urinary kidney injury molecule-1 (KIM-1) at 48 h, indicating sustained kidney injury. These mice also showed marked increases in plasma ferritin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at 8 h post-LPS versus nonprimed LPS-treated mice, consistent with a hyperinflammatory state. Poly(I:C) alone induced a rapid type I interferon (IFN) response, with elevated plasma IFNα, IFNβ, and renal expression by 4 h post injection. This model effectively replicates viral-bacterial coinfection and provides a valuable platform to dissect the mechanisms linking viral priming to dysregulated immune responses and acute tubular injury in sepsis. This two-hit murine model of viral-primed sepsis-associated acute kidney injury (SA-AKI) offers a novel and clinically relevant platform to dissect the immunopathogenic mechanisms linking viral-bacterial coinfections to severe kidney injury. By mirroring features of hyperinflammation and immune dysregulation seen in critically ill patients with SARS-CoV-2, influenza, and other viral infections, this model enables investigation of distinct viral-mediated inflammatory endotypes of SA-AKI, which may guide future efforts to develop targeted, endotype-specific therapies.
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