American journal of physiology. Renal physiology最新文献

{"title":"Nicotinamide ameliorates podocyte injury and albuminuria in adriamycin-induced nephropathy.","authors":"Kei Takahashi, Emiko Sato, Seiko Yamakoshi, Mizuki Ogane, Akiyo Sekimoto, Takamasa Ishikawa, Kiyomi Kisu, Yuji Oe, Koji Okamoto, Mariko Miyazaki, Tetsuhiro Tanaka, Nobuyuki Takahashi","doi":"10.1152/ajprenal.00297.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00297.2024","url":null,"abstract":"<p><p>Podocytes are key components of the glomerular filtration barrier, and their injury leads to proteinuria, chronic kidney disease (CKD), and nephrotic syndrome. Effective treatments for these conditions are not well established, and prevention of podocyte injury is a crucial challenge. Nicotinamide (NAM), a form of vitamin B3, has been reported to exert beneficial effects in various renal disease models due to its antioxidant and anti-inflammatory properties and its ability to replenish nicotinamide adenine dinucleotide (NAD⁺). However, its impact on adriamycin (ADR)-induced nephropathy, a model of nephrotic syndrome caused by podocyte injury, remains unclear. We investigated the effects of NAM administration in a mouse model of ADR nephropathy. BALB/c mice were intravenously administered ADR to induce nephropathy. In the NAM-treated group, mice received 0.6% NAM in drinking water ad libitum starting 7 days before ADR administration. After 14 days, NAM treatment decreased albuminuria, glomerular sclerosis, and podocyte injury, and reduced inflammation and oxidative stress markers in the kidneys. NAM and NAD⁺ levels were decreased in ADR-treated kidneys, and the expression of the NAD⁺-consuming enzymes SIRT1 and PARP-1 was decreased and increased, respectively. Nicotinamide N-methyltransferase expression was increased. NAM canceled these abnormalities. In cultured rat podocytes, NAD⁺ alleviated ADR-induced cytotoxicity, apoptosis, and inflammation. These findings suggest that NAM prevents ADR nephropathy and podocyte injury, likely through NAD⁺ replenishment.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544901","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 impact of maternal obesity on polycystic kidney disease progression in a mouse model.","authors":"Sarah J Miller, Kaitlyn Hill, Isabella Darby, Fariha Nusrat, Jacob E Friedman, Michael C Rudolph, Kurt A Zimmerman","doi":"10.1152/ajprenal.00227.2024","DOIUrl":"10.1152/ajprenal.00227.2024","url":null,"abstract":"<p><p>Due to the growing obesity epidemic in the United States, it is now estimated that approximately one third of all children are born to obese moms. These data, coupled with data indicating that obesity is associated with accelerated cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD), led us to hypothesize that maternal obesity may influence the rate of disease progression in offspring. To test this hypothesis, we induced maternal obesity by high-fat diet (HFD) feeding in the orthologous <i>Pkd1</i>^RC/RC mouse model of ADPKD and followed polycystic kidney disease (PKD) progression in offspring for up to 1 year. Surprisingly, and in contrast to our initial hypothesis, exposure to maternal obesity during pregnancy and lactation did not significantly impact PKD severity in offspring at 3 mo or 1 yr of age. In contrast, reexposure to HFD for ∼3 m beginning at 12 wk of age worsened PKD severity in female, but not male, offspring born to obese dams as measured by cystic index, cyst number, and cyst area. Despite worsened cystic parameters, fibrosis and blood urea nitrogen were not altered in these animals. Collectively, these findings indicate that maternal obesity may accelerate PKD severity in female offspring exposed to an obesogenic diet.<b>NEW & NOTEWORTHY</b> Due to the growing obesity pandemic, almost one third of all children are born to mothers with obesity; however, the impact of maternal obesity on polycystic kidney disease (PKD) is unknown. In this manuscript, we found that maternal obesity did not worsen PKD severity in <i>Pkd1</i>^RC/RC mice at 3 mo or 1 yr of age when weaned onto normal chow diet. However, rechallenging pups born to obese mothers worsened PKD severity in female but not male mice.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F316-F327"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191608","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":"Chronic kidney disease amplifies severe kidney injury and mortality in a mouse model of skin arsenical exposure.","authors":"Ritesh Kumar Srivastava, Amie Mark Traylor, Suhail Muzaffar, Stephanie K Esman, Reham H Soliman, Jasim Khan, Phoebe Warren, Subhashini Bolisetty, James F George, Anupam Agarwal, Mohammad Athar","doi":"10.1152/ajprenal.00139.2024","DOIUrl":"10.1152/ajprenal.00139.2024","url":null,"abstract":"<p><p>In previously published work, we elucidated the role of cutaneous arsenical exposure in promoting acute kidney injury (AKI) in adult healthy mice. Here, we determine whether preexisting chronic kidney disease (CKD) increases the severity of AKI. Following exposure to aristolochic acid (AA) (a nephrotoxic phytochemical in humans), mice manifested classical markers of CKD, including robust interstitial fibrosis and loss in kidney function. Skin challenge with phenylarsine oxide (PAO), a surrogate for warfare arsenicals, led to significantly worse kidney injury, as evidenced by tubulointerstitial fibrosis, glomerulosclerosis, a persistent loss of estimated glomerular filtration rate, and mortality in AA-induced CKD mice compared with mice without CKD. These PAO-challenged CKD mice exhibited enhanced production of serum/urine neutrophil gelatinase-associated lipocalin and a significant rise in serum creatinine along with histological markers of kidney injury, including brush border loss, tubular atrophy, cast formation, glomerular injury, and interstitial inflammatory cell infiltration. Serum cytokines IL-4, IL-6, IFN-γ, IL-12p70, TNF-α, and IL-18 significantly elevated in CKD mice following PAO exposure when compared with animals exposed to PAO alone. Furthermore, we found increased TUNEL-positive tubular cells in the kidneys of CKD mice following PAO exposure, suggesting enhanced PAO-mediated cell death in CKD mice. Mechanistically, we determined that DNA damage-regulated p53 signaling was a major mediator of cellular responses to PAO in CKD mice. In summary, our data demonstrate that CKD significantly increased the severity of AKI following exposure to arsenicals and suggest that human populations with preexisting CKD could be highly susceptible to arsenical-mediated kidney injury and associated morbidity and mortality.<b>NEW & NOTEWORTHY</b> Preexisting chronic kidney disease (CKD) predisposes experimental animals to augmented morbidity and mortality following cutaneous vesicant exposure. The mechanism underlying increased susceptibility to renal injury and associated morbidity involves the DNA damage-regulated p53 signaling pathway.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F328-F343"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482799","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":"Looking below the surface: using intravital imaging to decipher inflammatory renal disease and renal cell injury.","authors":"Michael J Hickey, Vaishnavi Sudhakar","doi":"10.1152/ajprenal.00321.2024","DOIUrl":"10.1152/ajprenal.00321.2024","url":null,"abstract":"<p><p>Renal function can be perturbed by a range of stimuli that cause cellular injury and inflammation in the kidney. These injurious and inflammatory processes are typically dynamic and progressive, involving the actions of highly migratory cells such as leukocytes and cellular responses that occur over time spans ranging from seconds to weeks. Understanding these dynamic responses has entailed the use of imaging technologies that allow visualization and capture of events over different time spans, ideally in intact organs in live, experimental animals. The technique that allows this is intravital imaging. Intravital imaging, particularly multiphoton intravital microscopy, has been crucial to the investigation of dynamic physiological and pathophysiological processes in the kidney for many years, driving key developments in our understanding of renal (patho)physiology. This includes the mechanisms of ultrafiltrate generation, the response to acute kidney injury, and how inflammatory leukocytes are recruited to and cause injury in the kidney. This review describes the key studies that have applied intravital imaging to the investigation of models of inflammatory renal disease. The responses examined include those restricted to the glomerulus and the effects of acute kidney injury on the tubulointerstitium. Future innovations and directions in this field of research are also discussed.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F418-F430"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367034","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":"Modulation of blood pressure by dietary potassium and sodium: sex differences and modeling analysis.","authors":"Melissa Stadt, Anita T Layton","doi":"10.1152/ajprenal.00222.2024","DOIUrl":"10.1152/ajprenal.00222.2024","url":null,"abstract":"<p><p>High Na⁺ intake has been linked to elevations in blood pressure, whereas K⁺ has the opposite effect. The underlying mechanisms involve complex interactions among renal function, fluid volume, fluid-regulatory hormones, vasculature, cardiac function, and the autonomic nervous system. These mechanisms are likely modulated by sex, given the known sex differences in blood pressure regulation and the higher prevalence of hypertension in men. The source of these observed sex differences may be traced to organ and tissue levels, given that kidney function, intrarenal renin-angiotensin system components, renal sympathetic nervous activity, and nitric oxide bioavailability all exhibit sex differences. To assess the functional impact of each of these sex differences, we developed sex-specific computational models to simulate whole-body Na⁺, K⁺, and fluid homeostasis, and the effects on blood pressure. The models describe the interactions among the renal system, cardiovascular system, gastrointestinal system, renal sympathetic nervous system, and renin-angiotensin-aldosterone system. Model simulations suggest that women's attenuated blood pressure response to hypertensive stimuli, including high Na⁺ intake, may be largely attributable to the female renal transporter abundance pattern. In addition, we investigated the causal link between high K⁺ intake and blood pressure reduction. The models simulate renal response to high K⁺ intake, including the immediate gastrointestinal feedforward signals to the kidneys to increase K⁺ excretion, and the longer-term response to decrease proximal fractional Na⁺ reabsorption and distal K⁺ reabsorption. With these assumptions, simulations of high K⁺ intake yielded kaliuresis, natriuresis, and a substantial reduction in blood pressure, even when combined with high Na⁺ intake.<b>NEW & NOTEWORTHY</b> Excessive dietary Na⁺ raises blood pressure, whereas a high K⁺ diet has the opposite effect. The underlying mechanisms are moderated by sex and involve multiple organs and tissues. How do high K⁺-induced alternations in kidney function lower blood pressure, and how do those mechanisms differ between men and women? To answer these questions, we conducted computer simulations to simulate whole-body fluid and electrolyte homeostasis, and the effects of Na⁺ and K⁺ intake on blood pressure.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F406-F417"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514472","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":"Recent advances on immunity and hypertension: the new cells on the kidney block.","authors":"John Henry Dasinger, Justine M Abais-Battad, Marice K McCrorey, Justin P Van Beusecum","doi":"10.1152/ajprenal.00309.2024","DOIUrl":"10.1152/ajprenal.00309.2024","url":null,"abstract":"<p><p>Over the past 50 years, the contribution of the immune system has been identified in the development of hypertension and renal injury. Both human and experimental animal models of hypertension have demonstrated that innate and adaptive immune cells, along with their cytokines and chemokines, modulate blood pressure fluctuations and end organ renal damage. Numerous cell types of the innate immune system, specifically monocytes, macrophages, and dendritic cells, present antigenic peptides to T cells, promoting inflammation and the elevation of blood pressure. These T cells and other adaptive immune cells migrate to vascular and tubular cells of the kidney and promote end-organ fibrosis, damage, and ultimately hypertensive injury. Through the development of high-throughput screening, novel renal and immune cell subsets have been identified as possible contributors and regulators of renal injury and hypertension. In this review, we will consider classical immunological cells and their contribution to renal inflammation, and novel cell subsets, including renal stromal cells, that could potentially shed new light on renal injury and hypertension. Finally, we will discuss how interorgan inflammation contributes to the development of hypertension and hypertension-related multiorgan damage, and explore the clinical implications of the immunological components of renal injury and hypertension.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F301-F315"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034878","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":"Sphingolipid signaling in kidney diseases.","authors":"Ningjun Li, Guangbi Li","doi":"10.1152/ajprenal.00193.2024","DOIUrl":"10.1152/ajprenal.00193.2024","url":null,"abstract":"<p><p>Sphingolipids are a family of bioactive lipids. The key components include ceramides, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate. Sphingolipids were originally considered to be primarily structural elements of cell membranes but were later recognized as bioactive signaling molecules that play diverse roles in cellular behaviors such as cell differentiation, migration, proliferation, and death. Studies have demonstrated changes in key components of sphingolipids in the kidneys under different conditions and their important roles in the renal function and the pathogenesis of various kidney diseases. This review summarizes the most recent advances in the role of sphingolipid signaling in kidney diseases.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F431-F443"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401017","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":"Integration of metabolomics and transcriptomics reveals the mechanism of TMEM30A downregulation induced FSGS podocyte injury.","authors":"Yanpei Hou, Sipei Chen, Yi Li, Liming Huang, Huijian Zhang, Min Yu, Lin Xiong, Xiang Zhong, Li Wang, Xianjun Zhu, Guisen Li, Lei Peng","doi":"10.1152/ajprenal.00201.2024","DOIUrl":"10.1152/ajprenal.00201.2024","url":null,"abstract":"<p><p>Podocyte injury plays a critical role in the pathogenesis and progression of focal and segmental glomerulosclerosis (FSGS). Transmembrane protein 30 A (TMEM30A) downregulation participates in podocyte injury. This study aimed to identify the critical pathways and molecules associated with the downregulation of TMEM30A in the context of FSGS podocyte injury. In our study, we found that TMEM30A and podocyte marker Synaptopodin were significantly downregulated in kidney tissues from patients with FSGS compared with those in normal controls. Using transcriptomic and metabolomic analyses, we characterized <i>Tmem30a</i> knockdown (KD) and normal mouse podocytes to identify differentially expressed genes and metabolites. Then, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Protein-Protein Interaction (PPI) network were constructed, and the differentially expressed genes and metabolites were enriched into glycolytic pathway. Furthermore, we found that the key glycolytic enzymes were downregulated in patients with FSGS, podocyte-specific <i>Tmem30a^LoxP/LoxP</i>; <i>NPHS2-Cre</i> mice, and <i>Tmem30a</i> KD mouse podocytes. For rescue experiments, shTmem30a-resistant cDNA (resTmem30a) was created to intervene <i>Tmem30a</i> KD mouse podocytes. And we observed that podocyte-related molecules were downregulated in the <i>Tmem30a</i> KD group, along with glycolysis-related molecules, but the resTmem30a partially reversed this trend. Our findings clarified that TMEM30A downregulation initiates podocyte injury by reducing glycolysis-related molecules (ALDOA, HK2, LDHA, and GAPDH) in FSGS and has implications for early diagnosis, prevention, and treatment.<b>NEW & NOTEWORTHY</b> This study aimed to identify the key pathways and molecules of TMEM30A downregulation involved in FSGS podocyte injury. Through comprehensive transcriptomic and metabolomic analyses, as well as in vivo and in vitro experiments, we discovered that the downregulation of TMEM30A triggers podocyte injury by decreasing the levels of glycolysis-related molecules, including ALDOA, HK2, LDHA, and GAPDH, in FSGS.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F389-F405"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191606","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":"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}