American journal of physiology. Renal physiology最新文献

{"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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082751","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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129752","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":"Indoxyl sulfate as a potential tubular function marker across kidney disease models.","authors":"Sabbir Ahmed, Shelley 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":"https://doi.org/10.1152/ajprenal.00107.2025","url":null,"abstract":"<p><p>Kidney tubular damage is a strong predictor of chronic kidney disease (CKD) 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 IRI) and acute (mouse and <i>in vitro</i> IRI) kidney disease. In 5/6^th 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-microglobuline (B2M) and cystatin C) better than with filtration markers (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 (HA) clearance correlated with plasma NGAL. Moreover, mass spectrometry imaging (MSI) analysis revealed higher cortical but lower medullary accumulation of IS in IRI mice kidneys compared to healthy controls, which was accompanied by a down regulation 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 transporters-related tubular function and may serve as sensitive clinical biomarkers for tubular dysfunction in kidney diseases.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","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":"https://doi.org/10.1152/ajprenal.00130.2025","url":null,"abstract":"<p><p>Renin-angiotensin-aldosterone system inhibitors (RAASi) 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 non-diabetic glomerular diseases remain unclear. Here, we investigated whether combining dapagliflozin (an SGLT2i) with ramipril (an angiotensin-converting enzyme Inhibitor) enhances kidney protection compared to 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 weeks of age. Mice were studied until 10 weeks of age (short-term, N=13-15/sex/group), 15 weeks of age (long-term, N=11-12/sex/group), or death (survival, N=8-12/sex/group). By 10 weeks, 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 weeks, D/R-treated mice had better renal function and histopathology than those on ramipril alone. D/R also extended survival compared to ramipril alone (median 157 vs. 125 days, p<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 to ramipril alone.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276997","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 organoid models of Polycystic Kidney Disease - challenges and future directions.","authors":"Humayra Afrin, Usama Qamar, Jielu Hao Robichaud, Mohamed Ellabbad, Peter C Harris, Navin Gupta","doi":"10.1152/ajprenal.00116.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00116.2025","url":null,"abstract":"<p><p>Kidney organoids are an increasingly established model of polycystic kidney disease (PKD). Derived from human pluripotent stem cells (hPSCs), organoids may be generated from induced pluripotent stem cells (iPSC) of patients that bear naturally occurring mutations or from CRISPR mutant hPSCs by virtue of their genetic tractability. PKD is the leading inheritable cause of kidney failure (KF), accounting for an ~5-10% of the kidney transplant and dialysis needs worldwide. PKD is a disorder of considerable genetic heterogeneity, comprised of typical adult-onset autosomal dominant (ADPKD) and fetal-onset autosomal recessive (ARPKD) forms which share pathomechanisms. Despite advances in our understanding of the genetic and molecular underpinnings of PKD, the limited clinical treatment options have raised concerns regarding the faithfulness of preclinical models. Kidney organoids have emerged as a promising platform to study PKD by mimicking human-specific responses, enabling personalized medicine, and supporting high-throughput screens. Yet valid criticisms have related to the relative immaturity of kidney organoids for modeling adult-onset forms of PKD, the faithfulness of organoids in modelling the cystic distribution of afflicted patients, and their batch-to-batch variability limiting experimental reproducibility. Here we summarize a decade of kidney organoid models of PKD, emphasizing their role in advancing translational and therapeutic applications while addressing their limitations and future potential.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276946","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 transplant injury associated with brain death is mediated by TNFα, independently of renal innervation.","authors":"T Pinto Coelho, P Erpicum, M Navez, M Vandermeulen, O Detry, F Jouret","doi":"10.1152/ajprenal.00109.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00109.2025","url":null,"abstract":"<p><p>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 <i>versus</i> circulatory death on kidney pathophysiology may help to prevent kidney transplant injury. We developed 3 rat models: 6h of BD (DBD, n=10); circulatory death (DCD, n=10) with 20min of warm ischemia; and 6-hour BD with renal denervation prior to BD (DNRV, n=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 pre-implantation biopsies matching our rat models (n=5 DBD; n=5 DCD). After BD, serum creatinine levels increased from 0.33 [0.31-0.38] to 0.61 [0.59-0.67]mg/dL (p<0.0001). Compared to DCD, DBD rats exhibited significantly higher levels of IL-6 (26.67 [19.10-32.35] <i>vs.</i> 10.32 [9.76-13.28]ng/mL, p=0.006) and TNFᵬ (21.98 [16.48-32.60] <i>vs.</i> 9.64pg/mL [7.96-11.13], p=0.0012), and lower levels of IL-10 (1.28 [1.11-1.65] <i>vs.</i> 1.79 [1.46-2.18]ng/mL, p=0.049). Differential expression analysis revealed that DBD kidneys exhibited CD11b-associated inflammation, caspase-3-mediated apoptosis, and TNFᵬ-driven injury (p=7.34×10^-7; z-score=2.475), while 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 (p=0.01 to 1.18×10^-7) in DBD compared to DCD, with 6 out of the top 15 pathways shared across species. Our findings highlight specific mechanisms affecting differently kidneys derived from DBD <i>vs.</i> DCD donors, with a potential role of TNFᵬ in BD-associated kidney injury. Kidney denervation prior to BD does not prevent kidney injury.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217832","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":"Adequate salt intake is essential for candesartan-treated rats to maintain renal function.","authors":"Anni Xie, Leijuan Xiao, Mingzhuo Zhang, Haonan Duan, Zhiyun Ren, Ping Wang, Yutao Jia, Jianteng Xu, Xueqi Chen, Mingda Liu, Weiwan Wang, Ying Xue, Jizhuang Lou, Xiaoyan Wang","doi":"10.1152/ajprenal.00313.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00313.2024","url":null,"abstract":"<p><p>Dietary salt restriction and angiotensin-II receptor-1 blockade (ARB) are commonly recommended for patients with renal and cardiovascular diseases. To explore what salt diet was suitable for the ARB users and what measurements predicted acute kidney injury (AKI), we evaluated the impact of low (0.02%, LS), normal (0.4%, NS), and high (2%, HS)-salt diets on renal function and urinary exosomal sodium-hydrogen exchanger-3 (NHE3), sodium-potassium-chloride cotransporter-2 (NKCC2), sodium-chloride cotransporter (NCC), and aquaporin-1 (AQP1) in candesartan-treated rats. All rats were given candesartan (1 mg/kg/day, ip) except as indicated. Relative to NS control, increased serum creatinine (SCr) but decreased creatinine clearance (Ccr) was observed in consecutive LS rats for 7 days with morphological kidney abnormalities. Similar changes at <i>day 3</i> were observed in the food-switching rats from NS to LS with elevated urine osmolality and creatinine but decreased sodium concentrations. Urinary exosomal NHE3, NKCC2, NCC, and AQP1 were increased in the consecutive LS rats with elevated serum renin, angiotensin-II, and aldosterone. They were increased at <i>day 1</i> in food-switching rats, 2 days earlier than changes in SCr and Ccr, but similar to urine kidney injury molecule-1. Renal and apical-membranous NHE3 and NKCC2 were increased, but AQP1 was decreased with decreased renal angiotensinogen and angiotensin-II receptor type I (AT1R). A moderate HS reversed the changes seen in food-switching rats in SCr, Ccr, and urinary exosomal measurements and improved the kidney morphological abnormalities. Thus, dietary salt restriction induces a prerenal/reversible kidney injury in candesartan-treated rats; urinary exosomal NHE3, NKCC2, NCC, and AQP1 may serve as early biomarkers for the damage.<b>NEW & NOTEWORTHY</b> Dietary salt restriction in candesartan-treated rats increases serum creatinine and urinary KIM-1 but decreases creatinine clearance with renal morphological abnormalities. Urinary exosomal NHE3, NKCC2, NCC, and AQP1 increase 2 days earlier than the changes of serum creatinine and creatinine clearance. Moderate high-salt diet reverses those changes with improved renal morphology. Extreme salt restriction should be avoided during candesartan treatment; urinary exosomal NHE3, NKCC2, NCC, and AQP1 may serve as early predictors of the acute kidney injury.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"328 6","pages":"F787-F799"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053426","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":"When ACE2 turns against the kidney: a paradox unveiled in heme-induced AKI.","authors":"Ying Fu, Zheng Dong","doi":"10.1152/ajprenal.00167.2025","DOIUrl":"10.1152/ajprenal.00167.2025","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F828-F829"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048660","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":"Altered renal vascular patterning reduces ischemic kidney injury and limits age-associated vascular loss.","authors":"Sarah R McLarnon, Samuel E Honeycutt, Pierre-Emmanuel Y N'Guetta, Yubin Xiong, Xinwei Li, Koki Abe, Hiroki Kitai, Tomokazu Souma, Lori L O'Brien","doi":"10.1152/ajprenal.00284.2024","DOIUrl":"10.1152/ajprenal.00284.2024","url":null,"abstract":"<p><p>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 (<i>Ntn1</i>) 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.<b>NEW & NOTEWORTHY</b> 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 (<i>Ntn1</i>) 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F876-F889"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058775","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":"Combined sedentarism and high-fat diet induce early signs of kidney injury in C57BL/6J mice.","authors":"Precious C Opurum, Stephen T Decker, Deborah Stuart, Alek D Peterlin, Venisia L Paula, Piyarat Siripoksup, Micah J Drummond, Alejandro Sanchez, Nirupama Ramkumar, Katsuhiko Funai","doi":"10.1152/ajprenal.00259.2024","DOIUrl":"10.1152/ajprenal.00259.2024","url":null,"abstract":"<p><p>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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F850-F860"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048659","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}