American journal of physiology. Renal physiology最新文献

{"title":"First Author Highlights.","authors":"","doi":"10.1152/ajprenal.2025.328.3.AU","DOIUrl":"https://doi.org/10.1152/ajprenal.2025.328.3.AU","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"328 3","pages":"i"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722975","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":"Genetic tools that target mechanoreceptors produce reliable labeling of bladder afferents and altered mechanosensation.","authors":"Emily L Tran, Sara A Stuedemann, Monica Ridlon, Olivia D Link, Kimberly P Keil Stietz, LaTasha K Crawford","doi":"10.1152/ajprenal.00151.2024","DOIUrl":"10.1152/ajprenal.00151.2024","url":null,"abstract":"<p><p>Mechanosensitive neurons are important sensors of bladder distention, but their role in urologic disease remains unclear. Our current knowledge about how disease alters bladder sensation comes from studies that focus primarily on peptidergic nociceptors, leaving our understanding of neuropeptide-negative mechanoreceptors incomplete. In this study, we found that a substantial proportion of neurofilament heavy (NFH)-positive A-fibers innervating the bladder was calcitonin gene-related peptide (CGRP)-negative, potentially representing uncharacterized mechanoreceptors. We then identified two genetic strategies that label mechanoreceptors in mouse skin and confirmed that they likewise label bladder afferents. Cre-mediated tdTomato reporter expression driven by tropomyosin receptor kinase B (<i>TrkB</i>), which labels Aδ mechanoreceptors in the skin, successfully labeled bladder nerve terminals. The majority of TrkB bladder afferents were CGRP-negative and NFH-positive, with more characteristic staining patterns seen at the level of the cell body. The <i>Ret</i> proto-oncogene (Ret) also produced robust labeling of bladder afferents, where colocalization with CGRP and NFH was consistent with multiple afferent subtypes. Because TrkB labeling was more specific for putative mechanoreceptors, we directly tested the role of TrkB neurons in bladder mechanosensation in vivo. Using an intersectional genetic strategy, we selectively ablated TrkB afferents and measured bladder responses to mechanical distention using anesthetized cystometry. Compared with controls, mice with ablated TrkB afferents required higher distention pressure to elicit voids. Interestingly, after ablation, distention also increased the frequency of nonvoiding contractions, a poorly understood phenotype of several urologic diseases. These genetic strategies comprise critical new tools to advance the study of mechanoreceptors in bladder function and urologic disease pathophysiology.<b>NEW & NOTEWORTHY</b> Most mechanosensitive afferents do not express markers of peptidergic nociceptors and therefore remain largely overlooked in studies of bladder dysfunction and disease. TrkB-mediated labeling of putative Aδ mechanoreceptors emerged as a valuable tool for the study of neuropeptide-negative bladder afferents with a confirmed role in bladder mechanosensation. Targeted neuronal ablation likewise validated an intersectional genetic strategy that can now directly test the role of TrkB mechanoreceptors in bladder physiology and disease.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F360-F374"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752646","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":"ERMP1 as a newly identified endoplasmic reticulum stress gatekeeper in chronic kidney disease.","authors":"Marta Correia de Sousa, Grégoire Arnoux, Raphaël Yvon, Christine Maeder, Margot Fournier, Noëlie Morin, Dobrochna Dolicka, Etienne Delangre, Miranda Türkal, Thibault Charlemagne, Sophie de Seigneux, David Legouis, Pierre Maechler, Eric Feraille, Michelangelo Foti, Monika Gjorgjieva","doi":"10.1152/ajprenal.00159.2024","DOIUrl":"10.1152/ajprenal.00159.2024","url":null,"abstract":"<p><p>Endoplasmic reticulum metallopeptidase 1 (ERMP1) is involved in the unfolded protein response (UPR) pathway in response to the endoplasmic reticulum (ER) stress. Given the pivotal role of ER stress in the pathogenesis of acute and chronic kidney diseases, we hypothesized that ERMP1 could be instrumental in the development of renal injury. In silico analysis of RNA sequencing datasets from renal biopsies were exploited to assess the expression of ERMP1 in the kidney under normal or pathological conditions. CRISPR-Cas9-mediated heterozygous genetic ablation of the exon 1 of <i>Ermp1</i> was performed in vivo, followed by histological analysis and assessment of renal injury and ER stress markers in the newly generated <i>Ermp1</i> knockout mouse model. In addition, knockdown and overexpression of ERMP1 were conducted in human tubular cells to investigate cell viability, metabolism, the UPR pathway, and ER Ca²⁺ release under these conditions. Our findings from patient datasets showed that ERMP1 is expressed in all renal cell types and is upregulated in chronic kidney disease. Further in silico investigations suggest a role for ERMP1 in renal development. ERMP1 knockout in mice revealed that homozygous loss of ERMP1 expression is lethal, whereas heterozygous loss exacerbated age-related chronic kidney alteration. In human tubular cells, ERMP1 knockdown decreased viability and metabolic rate, whereas overexpression conferred protection against ER stress. These results highlight the importance of ERMP1 in renal physiology and pathology and suggest that its upregulation could be a protective mechanism against excessive ER stress in renal tubule epithelial cells.<b>NEW & NOTEWORTHY</b> Our study reveals an increase in ERMP1 expression in acute and chronic kidney diseases, potentially serving as a protective mechanism against excessive ER stress. Conversely, a decline in ERMP1 expression in the kidney exacerbates age-related chronic kidney disease. Overall, the study enhances our understanding of the role of ERMP1 in kidney pathophysiology, paving the way for future research and therapeutic developments aimed at improving outcomes for patients with kidney diseases.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F375-F388"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054183","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":"Ribosomal s6 kinase is a mediator of aquaporin-2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib.","authors":"Richard S E Babicz, Noah Baylor, Abby Terlouw, Daphne A Faber, Kazuhiko Fukushima, Ricardo M Biondi, Richard Bouley, Dennis Brown","doi":"10.1152/ajprenal.00353.2024","DOIUrl":"10.1152/ajprenal.00353.2024","url":null,"abstract":"<p><p>Vasopressin (VP) activates protein kinase A (PKA), resulting in phosphorylation events and membrane accumulation of aquaporin-2 (AQP2). Epidermal growth factor receptor (EGFR) inhibition with erlotinib also induces AQP2 membrane trafficking with a phosphorylation pattern similar to VP, but without increasing PKA activity. Here, we identify the ribosomal s6 kinase (RSK) as a major mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. We found that RSK was expressed in collecting duct principal cells in rat kidneys. RSK inhibition with BI-D1870 blocked erlotinib-induced AQP2 serine 256 (S256) phosphorylation and membrane accumulation. CRISPR-generated RSK knockout (KO) cells failed to show increased S256 phosphorylation in response to erlotinib. Like PKA, RSK was able to phosphorylate AQP2 S256 in vitro. Inhibition of phosphoinositide-dependent kinase-1 (PDK1), a known activator of RSK, blocked erlotinib-induced AQP2 S256 phosphorylation and membrane accumulation. We conclude that RSK is a crucial terminal kinase phosphorylating AQP2 at S256 upon EGFR inhibition by erlotinib.<b>NEW & NOTEWORTHY</b> Epidermal growth factor receptor (EGFR) inhibition with erlotinib induces aquaporin-2 (AQP2) membrane accumulation with a phosphorylation pattern similar to vasopressin (VP). Here, we identify the ribosomal s6 kinase (RSK) as a major mediator phosphorylating AQP2 in this novel, erlotinib-induced pathway. In addition, we show that phosphoinositide-dependent kinase-1 (PDK1), a known activator of RSK, is implicated in this pathway: PDK1 inhibition blocks erlotinib-induced AQP2 S256 phosphorylation and membrane accumulation.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F344-F359"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018030","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":"The evolving concepts of KS-WNK1 effect on NCC activity.","authors":"María Chávez-Canales, Gerardo Gamba","doi":"10.1152/ajprenal.00272.2024","DOIUrl":"10.1152/ajprenal.00272.2024","url":null,"abstract":"<p><p>The field of the with-no-lysine kinases (WNKs) regulation of the thiazide-sensitive NaCl cotransporter (NCC) began at the start of the century with the discovery that mutations in two members of the family, WNK1 and WNK4, resulted in a condition known as familial hyperkalemic hypertension (FHHt). Since FHHt is the mirror image of Gitelman's syndrome that is caused by inactivating mutations of the SLC12A3 gene encoding NCC, it was expected that WNKs modulated NCC activity and that the increased function of the cotransporter is the pathophysiological mechanism of FFHt. This turned out to be the case. However, experiments over the first years generated unexpected observations that confused the field. Although most has been clarified, one issue still under a certain level of controversy is the role of an isoform of WNK1 that is only expressed in the kidney, almost entirely in the distal convoluted tubule, known as KS-WNK1. In this work, we present an overview of how the knowledge about the physiology of KS-WNK1 evolved over the years and propose explanations to understand its role in renal physiology.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F258-F269"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907978","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":"Intestinal barrier function declines during polycystic kidney disease progression.","authors":"Randee Sedaka, Caleb Lovelady, Emily Hallit, Branden Duyvestyn, Sejal Shinde, Aida Moran-Reyna, Goo Lee, Shinobu Yamaguchi, Craig L Maynard, Takamitsu Saigusa","doi":"10.1152/ajprenal.00058.2024","DOIUrl":"10.1152/ajprenal.00058.2024","url":null,"abstract":"<p><p>Most patients with autosomal dominant polycystic kidney disease (ADPKD) develop kidney cysts due to germline <i>PKD1</i> mutations. In the kidney, <i>Pkd1</i> loss impairs epithelial cell integrity and increases macrophage infiltration, contributing to cyst growth. Despite its role as the body's largest inflammatory cell reservoir, it has yet to be elucidated whether a similar phenotype presents in the intestines. We hypothesize that loss of <i>Pkd1</i> leads to a leaky intestinal epithelial barrier and increased inflammation, before rapid cystogenesis. Control and inducible, global <i>Pkd1</i> knockout (<i>Pkd1</i>KO) mice were euthanized at 3 and 6 mo of age (early and late stage) to evaluate kidney disease progression, small and large intestinal integrity, and inflammation. Early-stage <i>Pkd1</i>KO mice displayed mild cystic kidneys and tubular injury with preserved kidney function. Intestinal epithelial barrier was tighter in KO mice, which was associated with higher expression of cell-cell epithelial integrity markers. However, there was no evidence of local or systemic inflammation in either genotype. Late-stage <i>Pkd1</i>KO mice had severely cystic, impaired kidneys with increased expression of integrity markers, tubular injury, and inflammation. Intestinal epithelial barrier was leakier in late-stage <i>Pkd1</i>KO mice, accompanied by gene reduction of integrity markers, increased inflammation, and elevated water and sodium channel expression. Gut motility and fecal water excretion were increased in <i>Pkd1</i>KO compared with flox mice irrespective of age. Overall, kidney injury appears to precede intestinal injury in ADPKD, whereby the intestinal barrier becomes leaky as cystogenesis progresses.<b>NEW & NOTEWORTHY</b> Though autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder, this is the first study to explore a kidney-gut contribution to disease progression. We identified a tightened intestinal epithelial barrier in early PKD, which becomes leaky as kidneys become more cystic, accompanied by a sustained loss of fecal water. Given the only approved ADPKD therapeutic yields adverse aquaretic events, this study emphasizes the need to evaluate extrarenal water loss in patients before prescribing.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F218-F229"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856949","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":"A novel automated method for comprehensive renal cast quantification from rat kidney sections using QuPath.","authors":"Lauren Yunker, Megan Cleland Harwig, Alison J Kriegel","doi":"10.1152/ajprenal.00252.2024","DOIUrl":"10.1152/ajprenal.00252.2024","url":null,"abstract":"<p><p>The presence of tubular casts within the kidney serves as an important feature when assessing the degree of renal injury. Quantification of renal tubular casts has been historically difficult due to varying cast morphologies, protein composition, and stain uptake properties, even within the same kidney. Color thresholding remains one of the most common methods of quantification in the laboratory when assessing the percentage of renal casting; however, this method is unable to account for tubule casts stained a variety of colors. We have developed a novel method of automated cast quantification using the machine learning pixel classification tool within QuPath, an open-source software designed for digital pathology. We demonstrated the usability of this method in male and female Dahl salt-sensitive rats fed either low or high salt for 2 wk and male Sprague-Dawley rats treated with podotoxin puromycin aminonucleoside (PAN). Briefly, the pixel classifier was trained to identify kidney tissue, various cast color types, and slide backgrounds. Following the development of the pixel classifier, we applied it to the sample population and compared the results with those of other methods of cast quantification, including color thresholding and manual quantification. We found that the automated pixel classifier designed in QuPath was able to comprehensively quantify metachromatic tubular casts compared with color thresholding. This novel method of cast quantification provides researchers with the ability to reliably automate cast quantification that is both comprehensive and efficient.<b>NEW & NOTEWORTHY</b> We developed a method of automated renal tubule cast quantification using a machine learning-based pixel classifier within QuPath, an open-source image analysis software. The advantages of this approach are demonstrated by rigorous comparison of quantification methods on a set of Masson's trichrome-stained kidney sections from high- and low-salt fed salt-sensitive Dahl rats. Researchers are provided with step-by-step instructions for creating and training a pixel classifier in QuPath for application to image analysis.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F230-F238"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883824","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":"Pax inhibition: stressing proximal tubule for successful repair.","authors":"Hiroki Kitai, Devin Mulcrone, Tomokazu Souma","doi":"10.1152/ajprenal.00368.2024","DOIUrl":"10.1152/ajprenal.00368.2024","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F270-F271"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960167","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":"First Author Highlights.","authors":"","doi":"10.1152/ajprenal.2025.328.2.AU","DOIUrl":"https://doi.org/10.1152/ajprenal.2025.328.2.AU","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"328 2","pages":"i"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443008","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":"Guidelines for sex-specific considerations to improve rigor in renal research and how we got there.","authors":"Daria V Ilatovskaya, Benard Ogola, Jessica L Faulkner, Mykola Mamenko, Erin B Taylor, Elena Dent, Michael J Ryan, Jennifer C Sullivan","doi":"10.1152/ajprenal.00136.2024","DOIUrl":"10.1152/ajprenal.00136.2024","url":null,"abstract":"<p><p>Biological sex significantly influences disease presentation, progression, and therapeutic outcomes in chronic kidney disease and acute kidney injury. Sex hormones, including estrogen and testosterone, modulate key renal functions, including renal blood flow, glomerular filtration, and electrolyte transport, thereby affecting disease trajectory in a sex-specific manner. It is critical for researchers to understand why and how to integrate sex as a biological variable in data collection, analysis, and reporting. Integrating a sex-based perspective in kidney research will lead to more personalized and efficacious treatment strategies, optimizing therapeutic interventions for each sex. If addressed properly, the incorporation of sex as a biological variable (SABV) in renal research not only enhances the mechanistic understanding of renal disease, but also paves the way for precision medicine, promising improved clinical outcomes, and tailored treatment protocols for all patients. This paper is designed to serve as a guideline for researchers interested in rigorously incorporating sex as a biological variable in their studies.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F204-F217"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869792","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}