American Journal Of Physiology. Renal Physiology[JOURNAL]
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200 papers
Dapagliflozin, in addition to ramipril, ameliorates kidney disease progression in mice with Alport syndrome.
Miyata KN, Smith DM, Yamashita M … +9 more , Kim S, Yeargin FA, Beganovic M, Zhang SL, Chan JSD, Miner JH, Leal DN, Li JP, Bruno J
Am J Physiol Renal Physiol · 2025 Jul · PMID 40499560 · Full text
Renin-angiotensin-aldosterone system inhibitors (RAASis) have been the most extensively studied treatment for Alport syndrome, demonstrating established benefits for renal function and survival in both animals and humans...
Renin-angiotensin-aldosterone system inhibitors (RAASis) have been the most extensively studied treatment for Alport syndrome, demonstrating established benefits for renal function and survival in both animals and humans. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) slow chronic kidney disease progression, but their renoprotective mechanisms in nondiabetic glomerular diseases remain unclear. Here, we investigated whether combining dapagliflozin (an SGLT2i) with ramipril (an angiotensin-converting enzyme inhibitor) enhances kidney protection compared with ramipril alone in Col4α3 knockout (KO) mice, a murine model of Alport syndrome. Alport and wild-type (WT) mice (129S1/SvImJ) received dapagliflozin (1.5 mg/kg/day), ramipril (10 mg/kg/day), or both (D/R) via drinking water from 4 wk of age. Mice were studied until 10 wk of age (short-term, = 13-15/sex/group), 15 wk of age (long-term, = 11-12/sex/group), or death (survival, = 8-12/sex/group). By 10 wk, Alport mice exhibited weight loss, reduced glomerular filtration rate (GFR), increased BUN, and albuminuria, which were mitigated by ramipril and D/R but not by dapagliflozin. At 15 wk, D/R-treated mice had better renal function and histopathology than those on ramipril alone. D/R also extended survival compared with ramipril alone (median 157 vs. 125 days, < 0.01). Kidneys from D/R-treated mice exhibited reduced lipid accumulation and cell senescence. In conclusion, combining dapagliflozin with ramipril better preserves renal function and architecture and prolongs survival in Col4α3 KO Alport mice compared with ramipril alone. This study demonstrates that combining dapagliflozin with ramipril provides superior kidney protection and extends survival in Col4α3 KO Alport mice compared with ramipril alone. The combination therapy better preserves renal function, reduces both lipid accumulation and cell senescence, and decreases glomerulosclerosis and tubulointerstitial fibrosis. These findings highlight a potential new therapeutic approach for Alport syndrome and support further investigation of SGLT2 inhibitors in nondiabetic glomerular diseases.
Indoxyl sulfate as a potential tubular function marker across kidney disease models.
Ahmed S, Chen SXL, Lucas JPFE … +16 more , Knoppert SN, Harwood R, Faria J, Besseling PJ, Sparidans RW, Broekhuizen R, Westphal KGC, Mihăilă SM, Joles JA, Goldschmeding R, Nguyen TQ, Wilm B, Murray P, Sonnen AF, Gerritsen KGF, Masereeuw R
Am J Physiol Renal Physiol · 2025 Jul · PMID 40499558 · Publisher ↗
Kidney tubular damage is a strong predictor of chronic kidney disease progression. Tubular function involves nutrient reabsorption and active secretion via transporters, such as the organic anion transporters (OATs), to...
Kidney tubular damage is a strong predictor of chronic kidney disease progression. Tubular function involves nutrient reabsorption and active secretion via transporters, such as the organic anion transporters (OATs), to eliminate waste and metabolites, including protein-bound uremic toxins (PBUTs). In tubular dysfunction, PBUTs accumulate in plasma, which has been associated with many comorbidities. We hypothesized that PBUT plasma concentration and clearance are sensitive markers for tubular dysfunction. We evaluated this in experimental models of chronic [rat nephrectomy and mouse ischemia-reperfusion injury (IRI)] and acute (mouse and in vitro IRI) kidney disease. In 5/6th nephrectomy rats, plasma concentration and clearance of PBUTs correlated with urinary tubular injury markers [kidney injury molecule-1 (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), beta-2 microglobulin, and cystatin C] better than with filtration markers [glomerular filtration rate (GFR) and plasma creatinine, cystatin C, and urea]. Moreover, indoxyl sulfate (IS) plasma concentration and clearance correlated in the subgroup with the lowest tubular injury. In chronic IRI mice with mild to moderate injury, plasma IS and its clearance correlated with tubular atrophy scores, plasma NGAL, and NGAL excretion, whereas filtration markers did not correlate. In acute IRI mice, IS and hippuric acid clearance correlated with plasma NGAL. Moreover, mass spectrometry imaging analyses revealed higher cortical but lower medullary accumulation of IS in IRI mice kidneys compared with healthy controls, which was accompanied by a downregulation of proximal tubular transporters. After inducing IRI in vitro using a human kidney proximal tubule cell line, decreased OAT1-mediated transport of IS was confirmed. Together, these findings suggest that plasma IS and its clearance represent kidney transporter-related tubular function and may serve as sensitive clinical biomarkers for tubular dysfunction in kidney diseases. Plasma indoxyl sulfate (IS) and its clearance correlate better with tubular injury markers (Kim-1, NGAL) than filtration markers (GFR, creatinine) in chronic nephrectomy rats and chronic/acute ischemic injury (IRI) in mice. Mass spectrometry imaging showed higher cortical but lower medullary IS accumulation in mice, in which proximal tubular transporters were downregulated. In vitro organic anion transporter 1-mediated IS transport decreased post-IRI. Together, plasma IS and its clearance may be used as kidney tubular function markers.
Kidney transplant injury associated with brain death is mediated by TNFα, independently of renal innervation.
Pinto Coelho T, Erpicum P, Navez M … +3 more , Vandermeulen M, Detry O, Jouret F
Am J Physiol Renal Physiol · 2025 Jul · PMID 40459961 · Publisher ↗
Kidney transplant outcomes depend on various factors, including donor type. Brain death (BD) has been associated with significant kidney injury, with long-term sequelae. Deciphering the impact of BD versus circulatory de...
Kidney transplant outcomes depend on various factors, including donor type. Brain death (BD) has been associated with significant kidney injury, with long-term sequelae. Deciphering the impact of BD versus circulatory death on kidney pathophysiology may help to prevent kidney transplant injury. We developed three rat models: 6 h of BD [donor after brain death (DBD, = 10)]; donor after circulatory death (DCD, = 10) with 20 min of warm ischemia; and 6-h BD with renal denervation before BD (DNRV, = 6). RNA-Seq was performed on kidney tissue, followed by differential gene expression and pathway enrichment analyses. Circulating cytokines were measured by Luminex/ELISA. Our findings were validated in 10 human preimplantation biopsies matching our rat models ( = 5 DBD; = 5 DCD). After BD, serum creatinine levels increased from 0.33 [0.31-0.38] to 0.61 [0.59-0.67] mg/dL ( < 0.0001). Compared with DCD, DBD rats exhibited significantly higher levels of IL-6 (26.67 [19.10-32.35] vs. 10.32 [9.76-13.28] ng/mL, = 0.006) and TNFα (21.98 [16.48-32.60] vs. 9.64 pg/mL [7.96-11.13], = 0.0012) and lower levels of IL-10 (1.28 [1.11-1.65] vs. 1.79 [1.46-2.18] ng/mL, = 0.049). Differential expression analysis revealed that DBD kidneys exhibited CD11b-associated inflammation, Caspase-3-mediated apoptosis, and TNFα-driven injury ( = 7.34 × 10; -score = 2.475), whereas DCD kidneys activated EIF2/NRF2 stress-response pathways. Notably, denervation did not mitigate BD-induced injury. Human biopsies confirmed the positive enrichment of inflammatory pathways ( = 0.01 to 1.18 × 10) in DBD compared with DCD, with 6 out of the top 15 pathways shared across species. Our findings highlight specific mechanisms affecting differently kidneys derived from DBD versus DCD donors, with a potential role of TNFα in BD-associated kidney injury. Kidney denervation before BD does not prevent kidney injury. Kidney transplantation outcomes are influenced by donor type. Brain death has been associated with significant kidney injury, with long-term sequelae. We established two rat models mimicking human conditions of kidney donation after brain death or circulatory arrest. We identified TNFα as the main driver of BD-induced kidney injury, as validated in human pretransplant biopsies. Notably, kidney denervation before BD failed to prevent TNFα-mediated damage. Targeting TNFα signaling in DBD donors may improve transplant outcomes.
Intersecting transcriptomic landscapes of hypertension and kidney function in African American women.
Abbas M, Martin P, Lindsey ML … +5 more , Bennett ES, Brown TL, Nzerue C, Williams CR, Gaye A
Am J Physiol Renal Physiol · 2025 Jul · PMID 40445960 · Full text
Hypertension is a risk factor for chronic kidney disease (CKD) and disproportionately affects African American women, contributing to disparities in kidney health. The biological mechanisms connecting hypertension to red...
Hypertension is a risk factor for chronic kidney disease (CKD) and disproportionately affects African American women, contributing to disparities in kidney health. The biological mechanisms connecting hypertension to reduced kidney function remain poorly understood. This study leverages transcriptomic analyses to uncover shared molecular signatures associated with hypertension and kidney function, focusing on female-specific profiles. The study analyzed whole blood mRNA sequencing data from 344 African American women, divided into discovery ( = 172) and validation ( = 172) datasets, along with 147 African American men. Differential expression (DE) analyses were performed to identify mRNAs associated with hypertension and kidney function [measured as estimated glomerular filtration rate (eGFR)]. Female-specific findings were determined by comparing results between females and males. Pathway enrichment analyses were subsequently conducted to link the identified mRNAs to key biological mechanisms. Comparative analyses revealed unique transcriptomic profiles in females, underscoring the role of sex-specific factors in kidney function. DE analyses identified 95 female-specific genes associated with both hypertension and eGFR. Subsequent pathway enrichment analysis with the 95 genes revealed key pathways related to fibrosis, inflammation, lipid metabolism, and endothelial dysfunction. The list of 95 includes immune system players such as and that amplify inflammation and kidney injury. This study provides novel insights into the transcriptomic mechanisms underlying hypertension and kidney function in African American women. The findings emphasize the importance of addressing sex-specific molecular mechanisms associated with hypertension-related impaired kidney function. Future research should prioritize experimental validation and longitudinal studies to further elucidate these pathways. African American women experience a disproportionate burden of hypertension and chronic kidney disease, yet their molecular underpinnings remain understudied. This study uniquely integrates transcriptomic data from 344 African American women to uncover 95 female-specific genes jointly associated with hypertension and reduced kidney function. These genes implicate immune activation, cytoskeletal remodeling, and metabolic dysregulation as key contributors to renal decline. By identifying sex-specific molecular pathways, this work advances precision medicine approaches to address kidney health disparities.
Collecting duct-derived (pro)renin receptor contributes to 2-kidney, 1-clip-induced ischemic nephropathy and renovascular hypertension in mice.
Fu Z, Kaewsaro K, Soodvilai S … +2 more , Kimball A, Yang T
Am J Physiol Renal Physiol · 2025 Jul · PMID 40433846 · Publisher ↗
The 2-kidney, 1-clip (2K1C) Goldblatt model features overactivation of the systemic renin-angiotensin system (RAS) due to increased renin release from juxtaglomerular cells. However, no previous study has functionally as...
The 2-kidney, 1-clip (2K1C) Goldblatt model features overactivation of the systemic renin-angiotensin system (RAS) due to increased renin release from juxtaglomerular cells. However, no previous study has functionally assessed the potential involvement of the intrarenal RAS in this model. Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), where it plays a key role in regulating the intrarenal RAS under physiopathological conditions. In the present study, we used a mouse model of CD-specific deletion of PRR (CD PRR KO) to examine the role of CD PRR in the pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy and to further explore the underlying mechanism. Floxed and CD PRR KO mice underwent either a sham operation or clipping the left renal artery using a polyurethane cuff with an internal diameter of ∼2.7 mm for 1 mo. Subsequent analyses included blood pressure measurement, renal injury assessment, examination of epithelial Na channel (ENaC) subunit expression, and evaluation of plasma and intrarenal renin and angiotensin II levels. Clipping-induced hypertension and renal injury were both attenuated in CD PRR KO mice as compared with floxed controls. The protective phenotype of the null mice was paralleled with suppressed intrarenal renin levels. Moreover, renal medullary α-ENaC mRNA and protein expression were elevated by clipping in floxed mice, which was blunted in CD PRR KO mice. Together, these results suggest that the activation of CD PRR stimulates components of the intrarenal RAS and renal medullary α-ENaC, which result in increased tubular sodium reabsorption and thus contribute to 2K1C-induced renovascular hypertension and ischemic nephropathy. Nonspecifically targeting the RAS in renovascular hypertension and ischemic nephropathy is only partially effective and also limited by class toxicities of hyperkalemia and acute decline of renal function. Our results help understand the CD PRR-mediated local mechanism in the pathogenesis of renovascular hypertension and ischemic nephropathy, and also support CD PRR as a potential therapeutic target for selective inhibition of the intrarenal RAS to treat this devastating disease.
Early renal response to long-term salt loading: mitochondrial dysfunction, ER stress, and uromodulin accumulation in the kidney medulla.
Parveen H, Boder P, Mullen W … +5 more , Graham D, Van Agtmael T, Rampoldi L, Delles C, Mary S
Am J Physiol Renal Physiol · 2025 Jul · PMID 40424196 · Full text
Kidneys play a critical role in maintaining water and electrolyte balance, but prolonged salt loading can disrupt renal function by inducing osmotic and oxidative stress. Although high salt intake is well-known to contri...
Kidneys play a critical role in maintaining water and electrolyte balance, but prolonged salt loading can disrupt renal function by inducing osmotic and oxidative stress. Although high salt intake is well-known to contribute to hypertension and kidney damage, the early renal responses to mild, long-term salt intake, particularly in normotensive individuals, remain poorly understood. To address this knowledge gap, we investigated the effects of exposing normotensive Wistar Kyoto (WKY) rats to 1% NaCl over a 3-mo period, focusing on the medullary region and the adaptive cellular mechanisms in response to salt-induced stress. In addition, we examined the acute effects of 4 h of salt exposure on medullary tubules. The long-term salt intake did not significantly alter blood pressure or cause notable kidney damage but did lead to differential expression of proteins associated with mitochondrial dysfunction and endoplasmic reticulum (ER) stress in the renal medulla. Acute 4-h salt exposure triggered a rapid cellular response involving proteins linked to mitochondrial activity and oxidative stress responses. Both acute and chronic settings significantly reduced uromodulin (UMOD) excretion with altered trafficking indicating intracellular accumulation within medullary cells. This provides evidence that chronic salt loading disrupts normal protein handling without immediate renal injury, shedding light on adaptive mechanisms in the kidney to mitigate osmotic stress. These early adaptations provide insights into the mechanisms underlying salt-related renal pathologies and may inform therapeutic strategies for individuals susceptible to the effects of dietary salt. This study reveals that even in normotensive Wistar Kyoto rats, mild long-term salt loading induces early renal stress without overt kidney damage or hypertension. Novel findings include reduced uromodulin (UMOD) excretion and altered intracellular trafficking in the renal medulla, alongside mitochondrial dysfunction and endoplasmic reticulum stress. These data highlight UMOD as a sensitive marker of salt-induced renal adaptation and provide insights into early cellular responses to salt before clinical disease onset.
Local C1q/TNF-related protein 1 attenuates kidney inflammation and fibrosis by regulating macrophage activation.
Wang F, Gong Z, Yang N … +6 more , Zhou G, Jia M, Liu W, Zheng H, Bi G, Feng Y
Am J Physiol Renal Physiol · 2025 Jul · PMID 40424084 · Publisher ↗
Chronic kidney disease (CKD), characterized by persistent inflammation and progressive renal fibrosis, remains a major therapeutic challenge due to an incomplete understanding of its pathogenesis. Since C1q/TNF-related p...
Chronic kidney disease (CKD), characterized by persistent inflammation and progressive renal fibrosis, remains a major therapeutic challenge due to an incomplete understanding of its pathogenesis. Since C1q/TNF-related protein 1 (CTRP1) plays a potential role in fibrosis and inflammation in other tissues, we investigated the role of CTRP1 in patients and mice with CKD. Here CTRP1 expression was increased in plasma and decreased in the kidneys of patients with CKD. Upregulation of renal CTRP1 with adeno-associated-CTRP1 was associated with decreased renal fibrosis, inflammation, macrophage accumulation, and activation in mice models. Mechanistically, CTRP1 abolished the expression of transforming growth factor beta 1 (TGFβ1)-induced macrophage M2-associated genes and the transcriptional regulators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). In addition, upregulation of CTRP1 could partly downregulate lipopolysaccharide (LPS)-stimulated expression of proinflammatory genes in vitro. Conditioned media from TGFβ1-CTRP1-pretreated macrophages could less efficiently stimulate fibroblast activation compared with those from TGFβ1-pretreated macrophages. Thus, our study reveals local CTRP1 as a potential regulator of chronic inflammation and kidney fibrosis through regulating macrophage activation. Taken together, these findings support renal CTRP1 as a novel therapeutic target for CKD. Augmenting renal CTRP1 expression mitigates chronic inflammation and fibrosis by inhibiting pathological macrophage activation. These findings offer a novel mechanism of kidney inflammation and fibrosis. CTRP1 can be considered as a predictive marker and/or therapeutic target for patients with CKD.
Multiparametric quantitative magnetic resonance imaging of skeletal muscle in CKD.
Markewitz N, Wu C, Vandsburger M … +8 more , Paredes W, Duran S, Islam S, Noehren B, Fry CS, Peng Q, Abramowitz MK, Preserving Physical Function in CKD (PPF-CKD)Investigators
Am J Physiol Renal Physiol · 2025 Jul · PMID 40421837 · Full text
Skeletal muscle dysfunction causes functional decline and disability in patients with chronic kidney disease (CKD). Identification of muscle pathology before significant loss of physical function would be a major advance...
Skeletal muscle dysfunction causes functional decline and disability in patients with chronic kidney disease (CKD). Identification of muscle pathology before significant loss of physical function would be a major advance. Multiparametric, quantitative magnetic resonance imaging (qMRI) of seven leg muscle groups (3 thigh and 4 calf) was conducted in patients with CKD stages 4-5 ( = 6), end-stage kidney disease (ESKD, = 3), and healthy controls ( = 10) using a 3 Tesla MRI scanner. Measurements included T1 relaxation time in the rotating frame (T1ρ) and transverse relaxation time (T2) mapping, Dixon imaging of intramuscular fat content, diffusion tensor imaging (DTI) for muscle structure, and H-MR spectroscopy for intra- and extra-myocellular lipid (IMCL and EMCL, respectively) and physiologically relevant muscle metabolites. T1ρ and T2 times were prolonged and fat fraction (FF) was higher in patients with CKD compared with controls (differences of 4.99 ms (95% CI 1.71-8.27), 6.72 ms (95% CI 3.78-9.66), and 6.67% (95% CI 0.65-12.68), respectively). T1ρ and FF were similarly elevated across muscle groups, whereas T2 differences may have been greater in calf muscles. T1ρ and T2 were lower in patients with ESKD compared with CKD and similar to controls, consistent with prior histologic assessment of muscle fibrosis. No significant differences by CKD status were observed for DTI parameters. Compared with controls, IMCL was higher in patients with CKD, and trimethylamine and creatine concentrations were lower. In sum, multiparametric qMRI of skeletal muscle in patients with CKD noninvasively identified differences in metrics associated with fibrosis, fat infiltration, and metabolic dysregulation. In this study, we demonstrate that multiparametric, quantitative magnetic resonance imaging (qMRI) can quantify multiple distinct anatomic and pathologic features of skeletal muscle pathology in patients with CKD before significant functional decline. qMRI metrics of fibrosis and fat infiltration were elevated, and muscle metabolite concentrations were reduced, in patients with CKD compared with controls. This noninvasive approach offers a valuable alternative to traditional muscle biopsies for evaluating muscle health in patients with CKD.
Gliflozins in hypertension: basic mechanisms and clinical insights.
Rieg T, Liu R, Staruschenko A
Am J Physiol Renal Physiol · 2025 Jul · PMID 40421752 · Full text
Sodium-glucose cotransport (SGLT) inhibitors, or gliflozins, initially developed for managing type 2 diabetes mellitus, have emerged as promising therapeutic agents for hypertension, offering both cardiovascular and rena...
Sodium-glucose cotransport (SGLT) inhibitors, or gliflozins, initially developed for managing type 2 diabetes mellitus, have emerged as promising therapeutic agents for hypertension, offering both cardiovascular and renal protection. Recently, a dual SGLT1/SGLT2 inhibitor was approved for the treatment of heart failure (HF), including preserved and reduced ejection fraction. Clinical trials consistently demonstrate the ability of gliflozins to lower blood pressure (BP) and reduce cardiovascular events, particularly in patients with comorbid conditions such as chronic kidney disease and HF. However, these trials typically include hypertension as a comorbidity rather than as the primary condition, and data specific to patients with hypertension and without diabetes mellitus remain limited. This review highlights recent clinical and basic mechanistic insights into the antihypertensive effects of gliflozins. We discuss their influence on BP regulation, including modulation of renal sodium handling, the renin-angiotensin-aldosterone system, and vascular function. In addition, gliflozins exhibit significant anti-inflammatory and antifibrotic properties, reducing the risk of organ damage associated with chronic hypertension. Their metabolic benefits extend beyond glucose control, contributing to weight loss, and reduced uric acid levels, collectively supporting better cardiovascular outcomes. Accordingly, we also provide a brief overview of these metabolic effects. As ongoing research continues to explore the broader therapeutic applications of gliflozins, these agents may become integral to the management of hypertension, particularly in patients with complex cardiovascular and renal conditions.
Vasopressin V1a and V1b receptor antagonism does not affect the efficacy of tolvaptan in polycystic kidney disease.
Wang X, Jiang L, Nanayakkara K … +2 more , Hu J, Torres VE
Am J Physiol Renal Physiol · 2025 Jul · PMID 40418559 · Publisher ↗
Vasopressin plays a major role in the pathogenesis of autosomal dominant polycystic kidney disease (PKD), the fourth leading cause of end-stage kidney disease. The vasopressin V2 receptor (V2R) antagonist tolvaptan is th...
Vasopressin plays a major role in the pathogenesis of autosomal dominant polycystic kidney disease (PKD), the fourth leading cause of end-stage kidney disease. The vasopressin V2 receptor (V2R) antagonist tolvaptan is the only approved treatment. The role of vasopressin V1a and V1b receptors (V1aR and V1bR) has not been studied. mice were allocated to control and 5 experimental groups treated with tolvaptan, OPC21268 (V1aR antagonist), SSR149415 (V1bR antagonist), tolvaptan plus OPC21268, or tolvaptan plus SSR149415, from 4 to 16 wk of age, to compare their separate effects on PKD and to determine whether addition of OPC21268 or SSR149415 potentiates or hinders the therapeutic effect of tolvaptan. Tolvaptan significantly reduced total kidney volume (TKV) measured by MRI and rate of TKV growth. OPC21268 had no effect on PKD when administered alone. SSR149415 reduced TKV and TKV growth in female mice only. The sex-dependent effect may be due to the increased expression of the V2 and V1b receptors in the kidneys of female compared with male mice. When OPC21268 or SSR149415 was administered in combination with tolvaptan, TKV, TKV growth, kidney weights, kidney weights adjusted by body weight, cyst indices and volumes, and plasma urea concentrations were not different from those observed with administration of tolvaptan alone. These results indicate that the beneficial effects of tolvaptan in PKD are mainly mediated by the inhibition of V2 receptors and provide no support for clinical trials of V2R antagonists combined with either V1a or V1b receptor antagonists. Currently, the vasopressin V2 receptor antagonist tolvaptan is the only approved treatment for autosomal dominant polycystic kidney disease (ADPKD). It has been suggested that vasopressin acting on V1a or V1b receptors may also affect its development. We show that a V1aR antagonist has no effect in an ADPKD mouse model (Pkd1RC/RC), whereas a V2R antagonist has a modest attenuating effect in female mice only. Neither potentiates or hinders the beneficial effect of tolvaptan when administered in combination with this drug.
Logic-based modeling of inflammatory macrophage cross talk with glomerular endothelial cells in diabetic kidney disease.
Patidar K, Ford Versypt AN
Am J Physiol Renal Physiol · 2025 Jul · PMID 40418541 · Full text
Diabetic kidney disease is a complication in one out of three patients with diabetes. Aberrant glucose metabolism in diabetes leads to structural and functional damage in glomerular tissue and a systemic inflammatory imm...
Diabetic kidney disease is a complication in one out of three patients with diabetes. Aberrant glucose metabolism in diabetes leads to structural and functional damage in glomerular tissue and a systemic inflammatory immune response. Complex cellular signaling is at the core of metabolic and functional derangement. Unfortunately, the mechanism underlying the role of inflammation in glomerular endothelial cell dysfunction during diabetic kidney disease is not fully understood. Mathematical models in systems biology allow the integration of experimental evidence and cellular signaling networks to understand mechanisms involved in disease progression. This study developed a logic-based ordinary differential equations model to study inflammatory cross talk between macrophages and glomerular endothelial cells during diabetic kidney disease progression using a protein signaling network stimulated with glucose and lipopolysaccharide. This modeling approach reduced the biological parameters needed to study signaling networks. The model was fitted to and validated against available biochemical data from in vitro experiments. The model identified mechanisms for dysregulated signaling in macrophages and glomerular endothelial cells during diabetic kidney disease. In addition, the influence of signaling interactions on glomerular endothelial cell morphology through selective knockdown and downregulation was investigated. Simulation results showed that partial knockdown of VEGF receptor 1, PLC-γ, adherens junction proteins, and calcium partially improved intercellular junction integrity between glomerular endothelial cells. These findings contribute to understanding of signaling and molecular perturbations that affect glomerular endothelial cells in the early stage of diabetic kidney disease. This work provides a novel analysis of signaling cross talk between macrophages and glomerular endothelial cells in the early stage of diabetic kidney disease. A logic-based mathematical modeling approach identified vital signaling molecules and interactions that regulate glucose-mediated inflammation in glomerular endothelial cells and cause endothelial dysfunction in the diabetic kidney. Simulated interactions among vascular endothelial growth factor receptor 1, nitric oxide, and calcium significantly affected the intercellular junction proteins between glomerular endothelial cells.
Renal G protein-coupled estrogen receptor 1 regulates the epithelial sodium channel promoting natriuresis to a greater extent in females.
Nasci VL, Bopassa JC, Mironova E … +7 more , Rhoads M, Singh R, Buehler DP, Pollock DM, Pochynyuk OM, Stockand JD, Gohar EY
Am J Physiol Renal Physiol · 2025 Jul · PMID 40402842 · Full text
Hypertension prevalence is lower in women than in men. Enhanced renal sodium (Na) handling in females has been implicated in sex differences in hypertension. Epithelial Na channel (ENaC) is a key contributor to Na homeos...
Hypertension prevalence is lower in women than in men. Enhanced renal sodium (Na) handling in females has been implicated in sex differences in hypertension. Epithelial Na channel (ENaC) is a key contributor to Na homeostasis and is regulated by estrogen. Recent evidence suggests G protein-coupled estrogen receptor 1 (GPER1) evokes a female-specific natriuresis that involves endothelin-1 (ET-1). ET-1 has been shown to downregulate ENaC activity, but whether GPER1 regulates ENaC to modulate natriuresis is unknown. We tested the hypothesis that renal GPER1 functionally interacts with ENaC to promote natriuresis in a sex-specific manner. RNAscope confirmed coexpression of GPER1 and ENaC in rat renal tubules in a sex- and region-specific manner. Within the renal medulla, the number of ENaC/GPER1-positive tubules was greater in females than males. Renal medullary inhibition of ENaC or activation of GPER1 evoked comparable natriuresis in female rats. Electrophysiology revealed that pharmacological GPER1 activation downregulated ENaC activity, whereas genetic deletion of GPER1 from the principal cells of the collecting duct caused ENaC hyperactivity. The hyperactivity of ENaC caused by deletion of GPER1 in the principal cells was greater in female than male mice. RNAscope coexpression of aquaporin 2 (AQP2) and GPER1 confirmed the knockout (KO) of GPER1 from the principal cell (PC) in the kidney. Thus, renal GPER1 functionally interacts with ENaC in a sex-specific manner to promote natriuresis. This study identified GPER1 as a sex-specific upstream regulator of ENaC. We found that GPER1 and ENaC were coexpressed in the rat renal tubules in a sex and region-specific manner. Activation of GPER1 inhibited ENaC activity in isolated mouse collecting ducts, whereas deletion of GPER1 from the principal cells caused ENaC hyperactivity to a greater extent in female mice. Our data suggest GPER1 functionally interacts with ENaC in a sex-specific manner to promote natriuresis.
Identification and localization of adhesion G protein-coupled receptor expression in the murine kidney.
Steichen H, Xue J, Zaidman NA
Am J Physiol Renal Physiol · 2025 Jul · PMID 40372763 · Full text
Adhesion G protein-coupled receptors (AGPCRs) are a class of seven-transmembrane receptors that sense cell-to-cell and cell-to-extracellular matrix transient adhesive events. AGPCRs are physiologically relevant and regul...
Adhesion G protein-coupled receptors (AGPCRs) are a class of seven-transmembrane receptors that sense cell-to-cell and cell-to-extracellular matrix transient adhesive events. AGPCRs are physiologically relevant and regulate processes throughout the body. However, the physiological roles of many AGPCRs are undefined. Unlike G protein-coupled receptors (GPCRs) that bind soluble agonists, AGPCRs uniquely depend on extracellular interactions and stimuli to facilitate endogenous activation by a tethered peptide agonist. Therefore, it is paramount to determine the cellular localization of AGPCRs to begin unraveling their functional roles. In the present work, we have identified the most abundant AGPCRs expressed in the murine kidney and determined their cellular localization through a combination of single-nucleus RNA sequencing and RNAscope fluorescent in situ hybridization. We not only report the transcriptional abundance of six AGPCRs that are expressed in a cell-specific manner but also demonstrate that , a receptor with low but specific abundance by snRNAseq, is detected in a subset of principal cells by RNAscope. In addition, we identify cell-specific transcript variants of in the kidney, supporting a significant role of alternative splicing in AGPCR physiology. These data will assist in the generation of tissue- and cell-specific hypotheses and enable future investigations into the physiological roles of AGPCRs in the kidney and other tissues. Adhesion G protein-coupled receptors (GPCRs) are a unique class of receptors that regulate numerous physiological processes throughout the body. Here, we identify and localize the AGPCRs expressed in the mouse kidney using a multimodal approach. This work will provide a foundation for future investigations into the novel physiological roles of AGPCRs in the kidney.
Knockout of the V-ATPase interacting protein Tldc2 in B-type kidney intercalated cells impairs urine alkalinization.
Eaton AF, Danielson EC, Tu LJ … +2 more , Brown D, Merkulova M
Am J Physiol Renal Physiol · 2025 Jun · PMID 40358928 · Full text
Intercalated cells (ICs) are acid-base regulatory cells in the kidney collecting duct that excrete either acid or base into the urine in response to systemic cues. A-ICs deliver protons into the tubule lumen via an apica...
Intercalated cells (ICs) are acid-base regulatory cells in the kidney collecting duct that excrete either acid or base into the urine in response to systemic cues. A-ICs deliver protons into the tubule lumen via an apical proton pump (V-ATPase) and reabsorb base (bicarbonate) using the anion exchanger 1 (AE1) anion exchanger. B-ICs function in the opposite direction. They have basolateral V-ATPase and secrete bicarbonate into the lumen via the anion exchange protein pendrin. The function of a third IC subtype: the non-A, non-B IC, which has apical pendrin and apical V-ATPase, is less well understood. We previously reported that members of the TLDc protein family interact with the V-ATPase and may regulate its function. TLDc proteins exhibit a distinct expression pattern in the kidney with RNAseq showing high, differential expression of Tldc2 in B-ICs. Here, we show by RNAscope imaging that Tldc2 is indeed expressed in B-ICs but also in some non-A, non-B ICs. Using knockout () mice, we found that males and females had significantly lower urine pH than wild-type littermates and their ability to increase urine pH in response to a bicarbonate load was impaired. In addition, males developed hyperbicarbonatemia. kidneys contained fewer B-ICs than wild-type mice, but they were replaced by more non-A, non-B ICs; the number of A-ICs was unchanged. Finally, there was decreased basolateral accumulation of V-ATPase in B-ICs. These findings suggest that is a novel gene involved in renal acid-base regulation and in addition, may serve as a differentiation marker for B-ICs. Acid-base balance in the body is constantly changing but must be tightly controlled to be compatible with life. The kidney contains specialized cells that can excrete excess acid or base (bicarbonate) into the urine to maintain normal blood pH. The key protein involved in this process is called the V-ATPase. Here, we report that a novel V-ATPase interacting protein Tldc2 is critical for kidney bicarbonate secretion and is, therefore, a previously unrecognized acid-base regulatory gene.
Altered renal vascular patterning reduces ischemic kidney injury and limits age-associated vascular loss.
McLarnon SR, Honeycutt SE, N'Guetta PY … +6 more , Xiong Y, Li X, Abe K, Kitai H, Souma T, O'Brien LL
Am J Physiol Renal Physiol · 2025 Jun · PMID 40331791 · Full text
The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular...
The kidney vasculature has a complex arrangement, which runs in both series and parallel to perfuse the renal tissue and appropriately filter plasma. Recent studies have demonstrated that the development of this vascular pattern is dependent on netrin-1 secreted by renal stromal progenitors. Mice lacking netrin-1 () from these cells develop an arterial tree with stochastic branching, particularly of the large interlobar vessels. The current study investigated whether abnormalities in renal vascular patterning altered kidney function or response to injury. To examine this, we analyzed kidney function at baseline as well as in response to a model of bilateral ischemic injury and measured vascular dynamics in 7- to 8-mo-old mice. We found no differences in kidney function or morphology at baseline between mice with an abnormal arterial pattern compared with control. Interestingly, male and female mutant mice with stochastic vascular patterning showed a reduction in tubular injury in response to ischemia. Similarly, mutant mice also had a preservation of perfused vasculature with increased age compared with a reduction in the control group. These results suggest that guided and organized patterning of the renal vasculature may not be required for normal kidney function, but uncovers new implications for patterning in response to injury. Understanding how patterning and maturation of the arterial tree affects physiology and response to injury has important implications for enhancing kidney regeneration and tissue engineering strategies. Kidney vascular patterning is established through responses to guidance cues such as netrin-1; however, the significance of proper patterning to function and injury response remains unexplored. Here, utilizing a conditional knockout of netrin-1 () that displays persistent abnormal arterial patterning, we identify no significant disruptions to normal kidney physiology in adult animals but, surprisingly, less tubular damage in response to ischemic injury. This study uncovers new and significant implications for proper kidney vascular patterning.
Single-cell RNA sequencing and spatial transcriptomics reveal unique subpopulations of infiltrating macrophages and dendritic cells following AKI.
Melkonian AL, Cheung MD, Erman EN … +7 more , Moore KH, Lever JMP, Jiang Y, Yang Z, Lasseigne BN, Agarwal A, George JF
Am J Physiol Renal Physiol · 2025 Jun · PMID 40331777 · Publisher ↗
Kidney infiltrating macrophages (KIMs) and kidney dendritic cells (KDCs) are strongly associated with inflammation and fibrosis in acute kidney injury (AKI) and chronic kidney disease (CKD). Contrary to kidney resident m...
Kidney infiltrating macrophages (KIMs) and kidney dendritic cells (KDCs) are strongly associated with inflammation and fibrosis in acute kidney injury (AKI) and chronic kidney disease (CKD). Contrary to kidney resident macrophages (KRMs), which are self-renewing and present in the kidney prior to injury, KIMs are bone-marrow derived F4/80, CD11b macrophages that infiltrate the kidney during AKI. Here, we combined single-cell RNA sequencing (scRNAseq), spatial transcriptomics, and cellular indexing of transcriptomes and epitopes (CITE)-sequencing to elucidate temporal, spatial, and transcriptional characteristics of unique subpopulations of KIMs and KDCs in ischemia-induced AKI. scRNAseq revealed three KIM, two KDC, and one proliferative macrophage subpopulation. All six clusters were localized in unique, spatially constrained microenvironments and their locations were dynamically regulated following bilateral ischemia reperfusion injury. We showed that a specific Arginase 1-expressing KIM cluster infiltrates the kidney cortex at after ischemia. We also identified a macrophage subpopulation that expresses genes specific to cell proliferation that resides in the cortex in uninjured states and in the medulla at during the reparative phase of AKI. Gene ontology analysis revealed functional characteristics that distinguish each KIM and KDC population. By after ischemia, the transcriptional profiles of KIMs upregulate , and , markers normally limited to KRMs in quiescence and early AKI. Since KIMs and KDCs are profoundly involved in AKI, it is paramount that we understand their dynamics-temporally and spatially-and identify their key genes and surface protein markers to develop macrophage-specific therapeutics aimed toward targeting kidney disease. In this work, we fully characterized both single cell and spatial transcriptomes of kidney infiltrating macrophages (KIMs) and kidney dendritic cells (KDCs) following bilateral ischemia reperfusion injury. We also discovered distinct markers that differentiate KIMs from one another and kidney resident macrophages (KRMs). Finally, we show evidence suggesting that KIMs may reprogram and express genes previously limited to KRMs by following injury resolution.
High-phosphate causes endothelial extracellular matrix calcification by inducing endothelial cell mesenchymal transition and osteoblastic differentiation.
Ciceri P, Artioli L, Molinaro M … +10 more , Falleni M, Tosi D, Martinelli C, Santo N, Rondinone O, Miozzo M, Bianchi P, Gianelli U, Fontana L, Cozzolino M
Am J Physiol Renal Physiol · 2025 Jun · PMID 40327648 · Publisher ↗
Chronic kidney disease (CKD) and diabetes are prevalent conditions characterized by increased cardiovascular risk, also due to vascular calcification (VC). Vascular smooth muscle cells actively participate in VC; convers...
Chronic kidney disease (CKD) and diabetes are prevalent conditions characterized by increased cardiovascular risk, also due to vascular calcification (VC). Vascular smooth muscle cells actively participate in VC; conversely, the role of endothelial cells (ECs) has been less studied. Therefore, we investigated whether high-inorganic phosphate (Pi) has a procalcifying potential on ECs both in vitro and ex vivo, analyzing calcium deposition, mesenchymal transition [endothelial-to-mesenchymal transition (EndMT)], and osteoblastic differentiation. An ex vivo model of arterial ring was developed to study intima calcification. The effect of CKD serum and intima calcification in arteries of patients with CKD was also investigated. We demonstrated that Pi induces EC calcification dependent on Pi influx into the cell. Between and , Pi induces EndMT with an increase of both mesenchymal genes and markers together with the acquisition of migratory capabilities. From of Pi treatment, ECs differentiated into osteoblastic-like cells with the upregulation of osteoblastic genes and proteins together with a modification of extracellular matrix that acquires osteochondrogenic characteristics. Interestingly, EndMT modulation decreased calcium deposition, suggesting a relationship between the two differentiation processes. Moreover, in an ex vivo model of arterial ring intimal calcification, Pi induced endothelial calcification and expression of osteogenic markers. Moreover, in vitro, CKD serum increased calcium deposition by exacerbating EndMT and simil-osteoblastic differentiation. Finally, intima calcification and EC osteoblastic transformation were detected in the arteries of patients with CKD. In this study, we demonstrated that both Pi and CKD induce intimal calcification and that endothelial calcification is an active process characterized by EndMT and osteoblastic differentiation. The significance of this study is the demonstration that, in chronic kidney disease (CKD), intima is not a passive actor but undergoes deep changes up to osteoblastic-like differentiation and calcification. Considering these new findings, the vessel probably needs to be considered as a unique organ in the pathogenesis of vascular calcification (VC). This new point of view may help in finding strategies and implementing targeted therapies to delay or block the development of VC in CKD.
Combined sedentarism and high-fat diet induce early signs of kidney injury in C57BL/6J mice.
Opurum PC, Decker ST, Stuart D … +7 more , Peterlin AD, Paula VL, Siripoksup P, Drummond MJ, Sanchez A, Ramkumar N, Funai K
Am J Physiol Renal Physiol · 2025 Jun · PMID 40327334 · Full text
Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. Obesity and sedentary behavior contribute to the development of CKD, though mechanisms by which this occurs are poorly unders...
Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. Obesity and sedentary behavior contribute to the development of CKD, though mechanisms by which this occurs are poorly understood. This knowledge gap is worsened by the lack of a reliable murine CKD model that does not rely on injury, toxin, or gene deletion to induce a reduction in kidney function. High-fat diet (HFD) feeding alone is insufficient to cause reduced kidney function until later in life. Here, we used a small mouse cage (SMC), a recently developed mouse model of sedentariness, to study its effect on kidney function. Wild-type C57BL/6J male mice were housed in sham or SMC housing for 6 mo with HFD in room (22°C) or thermoneutral (30°C) conditions. Despite hyperinsulinemia induced by the SMC + HFD intervention, kidneys from these mice displayed normal glomerular filtration rate. However, the kidneys showed early signs of kidney injury, including increases in collagen I and neutrophil gelatinase-associated lipocalin transcripts, as well as fibrosis by histology, primarily in the inner medullary/papilla region. High-resolution respirometry and fluorometry experiments showed no statistically significant changes in the capacities for respiration, ATP synthesis, or electron leak. These data confirm the technical challenge in modeling human CKD. They further support the notion that obesity and a sedentary lifestyle make the kidneys more vulnerable, but additional insults are likely required for the pathogenesis of CKD. Physical inactivity is a risk factor for chronic kidney disease. Our laboratory recently developed a new mouse model of physical inactivity (small mouse cage housing) that more closely recapitulates the metabolic disturbances that occur with sedentary behavior. In this paper, we performed an in-depth phenotyping of kidney function and metabolic parameters in response to small mouse cage housing.
Renal antigen-presenting cells from ANG II hypertensive donors transfer blood pressure and promote sodium retention.
Araos P, León P, Gallegos-Pérez I … +16 more , Schäfer C, García-Betancourt R, Salas-Huenuleo E, Prado C, Barrientos V, Liberona J, Kojimahara T, Figueroa SM, Amador CA, Carreño LJ, Kogan MJ, Gonzalez AA, Pacheco R, Alzamora R, Brooks HL, Michea L
Am J Physiol Renal Physiol · 2025 Jul · PMID 40327323 · Publisher ↗
Antigen-presenting cells (APCs) are present in the renal interstitium and may modulate tubular function. We hypothesize that angiotensin II (Ang II) induces a prohypertensive phenotype in renal APCs, contributing to decr...
Antigen-presenting cells (APCs) are present in the renal interstitium and may modulate tubular function. We hypothesize that angiotensin II (Ang II) induces a prohypertensive phenotype in renal APCs, contributing to decreased natriuresis and hypertension. We evaluated the role of renal APCs as modulators of blood pressure (BP) in CD11c.DOG mice injected with diphtheria toxin (DT). Elimination of 70% of renal APCs by DT prevented the increase in BP, cardiac hypertrophy, decreased natriuresis, and sodium-potassium-chloride cotransporter type II (NKCC2) activation. Second, we compared the effect of the adoptive transfer of renal and splenic APCs on BP and natriuresis in wild-type mice. Renal APCs from Ang II mice induced a transient BP increase and reduced natriuresis. In contrast, renal APCs from control mice or splenic APCs from control or Ang II-infused mice did not modify BP or natriuresis. In CD11c.DOG mice depleted of dendritic cells (DCs), the adoptive transfer of renal APCs from Ang II-infused mice increased the BP. However, RAG1 knockout mice, devoid of T cells, did not present an increase in BP after the adoptive transfer of renal APCs of Ang II-infused mice. Renal APCs from Ang II-infused mice showed increased NOX2, SGK1, and pro-inflammatory cytokine expression compared with control renal APCs. Cell-tracking experiments of transferred renal APCs into a normotensive host showed preferential homing to the host kidneys and higher receptor expression for the renal-homing chemokine, fractalkine (CX3CR1). We conclude that renal APCs acquire a prohypertensive phenotype due to high Ang II levels, conferring the ability to modulate renal sodium handling. Ablation of APCs prevented Ang II-induced hypertension, NKCC2 activation, and preserved natriuresis. Transfer of renal APCs from Ang II-mice increased BP and reduced natriuresis in recipient mice; renal APCs from normotensive mice or splenic APCs from Ang II-infused mice had no effect. The effect of renal APCs was dependent on the presence of T cells. Renal APCs from Ang II-mice showed preferential destination to the kidney and increased expression of cytokines.
When ACE2 turns against the kidney: a paradox unveiled in heme-induced AKI.
Fu Y, Dong Z
Am J Physiol Renal Physiol · 2025 Jun · PMID 40323194 · Publisher ↗
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