American journal of physiology. Renal physiology最新文献

{"title":"Macula Densa Nitric Oxide Synthase 1β Restoration by Kidney Alkalization Enhances Renal Graft Outcomes.","authors":"Colby L Parris, Catherine Liu, Alka Rani, Minh H Tran, MingHua Li, Carlos Esquivel, Andrea M Oropeza, Lei Wang","doi":"10.1152/ajprenal.00195.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00195.2025","url":null,"abstract":"<p><p>Ischemia-reperfusion injury (IRI) remains a critical challenge to the survival of kidney transplantation (KTX) graft, with no effective prevention or treatment strategies currently available. Neuronal nitric oxide synthase β (NOS1β), the predominant splice variant of NOS1 and the main source of NO in the macula densa (MD), mediates tubuloglomerular feedback and regulates glomerular filtration rates. NOS1β activity in the MD is influenced by renal pH; however, the role of pH-dependent regulation of NOS1β in mitigating IRI and protecting transplanted kidney graft function remains unclear. To explore this, C57BL/6J mice were given oral NaHCO₃ or NaCl for two weeks before KTX. Blood and urine pH, NOS1β expression, NO levels, and transplant outcomes were evaluated. MD-specific NOS1 knockout (MD-NOS1KO) mice were used to assess the direct role of NOS1β. NOS1β expression decreased by approximately 60% three days post-KTX. MD-NOS1β deletion exacerbated graft injury. NOS1β activities showed a strong tubular pH dependence, with maximal activity near pH 8.0. Bicarbonate treatment increased NOS1β expression in the MD by 65% and significantly improved graft outcomes, lowering plasma creatinine by ~30% relative to NaCl-treated group. These protective effects were absent in MD-NOS1βKO mice. Proteomic analysis revealed 718 differentially expressed proteins, with several showing enrichment in NO signaling, tissue repair, and inflammatory response pathways. In summary, MD-NOS1β downregulation after transplantation contributes to graft injury. Raising renal pH with bicarbonate enhances NOS1β activity and protects graft function, suggesting a potential therapeutic strategy to reduce IRI in kidney transplants.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local C1q/TNF-related protein 1 attenuates kidney inflammation and fibrosis by regulating macrophage activation.","authors":"Fei Wang, Zhe Gong, Nianjia Yang, Gang Zhou, Mengxue Jia, Wenjin Liu, Huaqing Zheng, Guangyu Bi, Ye Feng","doi":"10.1152/ajprenal.00346.2024","DOIUrl":"10.1152/ajprenal.00346.2024","url":null,"abstract":"<p><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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F71-F86"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vasopressin V1a and V1b receptor antagonism does not affect the efficacy of tolvaptan in polycystic kidney disease.","authors":"Xiaofang Wang, Li Jiang, Kavini Nanayakkara, Jinghua Hu, Vicente E Torres","doi":"10.1152/ajprenal.00350.2024","DOIUrl":"10.1152/ajprenal.00350.2024","url":null,"abstract":"<p><p>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. <i>Pkd1</i>^RC/RC 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 <i>Pkd1</i>^RC/RC 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F20-F31"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collecting duct-derived (pro)renin receptor contributes to 2-kidney, 1-clip-induced ischemic nephropathy and renovascular hypertension in mice.","authors":"Ziwei Fu, Kannaree Kaewsaro, Sunhapas Soodvilai, Alex Kimball, Tianxin Yang","doi":"10.1152/ajprenal.00340.2024","DOIUrl":"10.1152/ajprenal.00340.2024","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F46-F58"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and localization of adhesion G protein-coupled receptor expression in the murine kidney.","authors":"Hailey Steichen, Jianxiang Xue, Nathan A Zaidman","doi":"10.1152/ajprenal.00134.2025","DOIUrl":"10.1152/ajprenal.00134.2025","url":null,"abstract":"<p><p>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 <i>Adgrf1</i>, 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 <i>Adgrf5</i> 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F11-F19"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12207994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal antigen-presenting cells from ANG II hypertensive donors transfer blood pressure and promote sodium retention.","authors":"Patricio Araos, Pablo León, Ignacio Gallegos-Pérez, Carolina Schäfer, Richard García-Betancourt, Edison Salas-Huenuleo, Carolina Prado, Víctor Barrientos, Jessica Liberona, Tomohiro Kojimahara, Stefanny M Figueroa, Cristián A Amador, Leandro J Carreño, Marcelo J Kogan, Alexis A Gonzalez, Rodrigo Pacheco, Rodrigo Alzamora, Heddwen L Brooks, Luis Michea","doi":"10.1152/ajprenal.00212.2024","DOIUrl":"10.1152/ajprenal.00212.2024","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F87-F98"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal G protein-coupled estrogen receptor 1 regulates the epithelial sodium channel promoting natriuresis to a greater extent in females.","authors":"Victoria L Nasci, Jean C Bopassa, Elena Mironova, Megan Rhoads, Ravneet Singh, Dennis P Buehler, David M Pollock, Oleh M Pochynyuk, James D Stockand, Eman Y Gohar","doi":"10.1152/ajprenal.00019.2025","DOIUrl":"10.1152/ajprenal.00019.2025","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1-F10"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early renal response to long-term salt loading: mitochondrial dysfunction, ER stress, and uromodulin accumulation in the kidney medulla.","authors":"Humaira Parveen, Philipp Boder, William Mullen, Delyth Graham, Tom Van Agtmael, Luca Rampoldi, Christian Delles, Sheon Mary","doi":"10.1152/ajprenal.00348.2024","DOIUrl":"10.1152/ajprenal.00348.2024","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F112-F127"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indoxyl sulfate as a potential tubular function marker across kidney disease models.","authors":"Sabbir Ahmed, Shelley X L Chen, Jacqueline P F E Lucas, Sebastiaan N Knoppert, Rachel Harwood, João Faria, Paul J Besseling, Rolf W Sparidans, Roel Broekhuizen, Koen G C Westphal, Silvia M Mihăilă, Jaap A Joles, Roel Goldschmeding, Tri Q Nguyen, Bettina Wilm, Patricia Murray, Andreas F-P Sonnen, Karin G F Gerritsen, Rosalinde Masereeuw","doi":"10.1152/ajprenal.00107.2025","DOIUrl":"10.1152/ajprenal.00107.2025","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F160-F177"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dapagliflozin, in addition to ramipril, ameliorates kidney disease progression in mice with Alport syndrome.","authors":"Kana N Miyata, Denise M Smith, Michifumi Yamashita, Shimok Kim, F Andrea Yeargin, Melisa Beganovic, Shao-Ling Zhang, John S D Chan, Jeffrey H Miner, Daniel N Leal, Jian-Ping Li, Jonathan Bruno","doi":"10.1152/ajprenal.00130.2025","DOIUrl":"10.1152/ajprenal.00130.2025","url":null,"abstract":"<p><p>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, <i>n</i> = 13-15/sex/group), 15 wk of age (long-term, <i>n</i> = 11-12/sex/group), or death (survival, <i>n</i> = 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, <i>P</i> < 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F178-F189"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12244471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}