American journal of physiology. Renal physiology最新文献

{"title":"Renal ischemia/reperfusion injury triggers proximal tubular apoptosis and NHE3 dysfunction via p38MAPK/ezrin signaling pathway.","authors":"Juliana Martins da Costa-Pessoa, Mariana Charleaux de Ponte, Heitor Macedo Braz, Mário Costa Cruz, Guilherme Lopes Gonçalves, Maria Oliveira-Souza","doi":"10.1152/ajprenal.00338.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00338.2024","url":null,"abstract":"<p><p>Acute kidney injury (AKI) induced by ischemia/reperfusion (IR) contributes to a high rate of morbidity and mortality in many clinical settings. We hypothesized that IR-induced proximal tubule (PT) injury is associated with inflammation and apoptosis and that PT cell injury may impair Na⁺/H⁺ exchanger isoform 3 (NHE3) activity. This study aimed to investigate the relationship between PT injury and NHE3 activity, analyzing the contribution of the p38MAPK/ezrin signaling pathway. To this end, we used <i>in vivo</i> and <i>in vitro</i> models of IR. For the <i>in vivo</i> approach, eight-week-old C57BL/6J mice were subjected to bilateral kidney IR and compared with the sham group. <i>In vitro</i>, TKPTS cells (mouse proximal tubular cell line) were subjected to IR by treatment with antimycin A (5 μM) and/or SB203580 (1 μM, p38MAPK inhibitor) or NSC305787 (3.2 μM, ezrin phosphorylation inhibitor) and compared with respective controls. Renal IR in mice resulted in PT injury, severe inflammation, increased p38MAPK activation, reduced p-ezrin immunostaining, and decreased colocalization of NHE3 with both villin and p-ezrin. Similarly, <i>in vitro</i> IR caused cell apoptosis, increased p38MAPK activation, induced translocation of ezrin from the membrane to the cytosol, and reduced NHE3 activity. Thus, these findings suggest that in ischemic AKI, tubulointerstitial injury is driven by inflammation and apoptosis, mediated through p38MAPK activation and altered ezrin function, ultimately impairing NHE3 activity and exacerbating cell injury.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562326","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":"Inhibition of methylthioadenosine phosphorylase protects from experimental acute kidney injury.","authors":"Afaf Saliba, Yidong Chen, Jonathan W Nelson, Abhinav Vetcha, Wei Wei Wang, Li Kang, Nagarjunachary Ragi, Soumya Maity, Hamid Rabb, W Brian Reeves, Kumar Sharma","doi":"10.1152/ajprenal.00138.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00138.2025","url":null,"abstract":"<p><p>Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism that may influence cellular responses to injury. We evaluated the effects of prophylactic MTAP inhibition in mouse models of ischemia-reperfusion and cisplatin-induced acute kidney injury (AKI). MTAP inhibition was confirmed by accumulation of methylthioadenosine (MTA). Treated mice showed reduced renal injury and decreased tubular damage. Transcriptomic analysis revealed protection from inflammatory and stress pathways, while maintaining oxidative phosphorylation, fatty acid metabolism, and epithelial integrity-related genes. Analysis of human single-cell RNA-seq data from the Kidney Precision Medicine Project indicated that MTAP is highly expressed in kidney injury marker-positive adaptive proximal tubule cells, which display both reparative and maladaptive features during AKI. These findings highlight MTAP as a potential therapeutic target for modulating injury responses in AKI.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556135","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":"Kidney organoids demonstrate that PTH1R drives a cystogenic cAMP-pPKA-pCREB axis in developmental Polycystic Kidney Disease.","authors":"Humayra Afrin, Jielu Hao, Usama Qamar, Peter C Harris, Navin Gupta","doi":"10.1152/ajprenal.00056.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00056.2025","url":null,"abstract":"<p><p>Human pluripotent stem cell-derived kidney organoids have demonstrated utility in modeling kidney development and genetic disease. Autosomal recessive polycystic kidney disease (ARPKD) is an inherited developmental cystic kidney disease of high morbidity and mortality that lacks directed therapy. To overcome the limitations of animal models and stimulate drug discovery, ARPKD organoids have previously been subject to well-described cystogenic mechanisms for use in therapeutic screens. While these studies have validated genotype-phenotype correlations and cystogenic response of ARPKD organoids as similar to existing <i>in vitro</i> models, novel cystogenic mechanisms that expand potential therapeutic targets have yet to be uncovered. Here we use a combination of human induced pluripotent stem cell (iPSC)-derived ARPKD and isogenic wild-type organoids, native kidney and organoid single cell RNA sequencing, decedent human ARPKD tissue, and targeted mechanistic studies to describe PTH1R as a stimulatory G-protein coupled receptor which instigates a cystogenic signaling cascade in developmental cystic kidney disease. Our findings demonstrate the utility of kidney organoids as an <i>in vitro</i> model for pathomechanisms of rare diseases which lack faithful animal models.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556136","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":"Mechanisms of anti-VEGF therapy-induced kidney injury: current insights and future perspectives in combination with immune checkpoint inhibitors.","authors":"Tom Uyl, Abigail Ngo, Delaney Pratt, Isabella Cortez, Ron Mathijssen, Jorie Versmissen, A H Jan Danser, Katrina Maree Mirabito Colafella","doi":"10.1152/ajprenal.00081.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00081.2025","url":null,"abstract":"<p><p>The formation of new blood vessels is crucial for tumour and metastatic progression. Consequently, targeted therapies directed towards the vascular endothelial growth factor (VEGF) pathway have significantly improved treatment outcomes in several malignancies. These treatment modalities are frequently used in current oncologic practice, as monotherapy, or in combination with other anti-cancer regimens such as immune checkpoint inhibitors (ICIs), to enhance the anti-cancer effects. Despite their proven efficacy, anti-VEGF therapies are also known to cause substantial renal toxicity. Common renal side effects include hypertension, proteinuria, renal dysfunction, thrombotic microangiopathy, and in some cases, renal failure. These adverse effects pose significant challenges in clinical practice, as kidney damage can lead to lower dosing of anti-cancer treatment and compromise quality of life. The mechanisms underlying kidney toxicity associated with anti-VEGF therapies, including in combination with ICIs, are poorly understood. A deeper understanding of these mechanisms is essential for mitigating kidney damage and preserving kidney function during treatment. This review aims to explore the role of VEGF in renal physiology, the incidence of renal toxicities associated with anti-VEGF therapies, and the potential mechanisms driving these toxicities, with particular emphasis on the endothelin, nitric oxide, and prostanoid pathways. Additionally, the review will address the renal effects observed when anti-VEGF therapies are combined with ICIs, as both treatment modalities are independently associated with kidney-related adverse effects, along with the underlying mechanisms involved.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556137","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":"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":"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":"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164288","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}