American journal of physiology. Renal physiology最新文献

{"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":"Endothelin-1 signaling in the kidney: recent advances and remaining gaps.","authors":"Abigail J Brooks, María Del Carmen Gallego-López, Carmen De Miguel","doi":"10.1152/ajprenal.00304.2024","DOIUrl":"10.1152/ajprenal.00304.2024","url":null,"abstract":"<p><p>The involvement of endothelin-1 (ET-1) in the maintenance of kidney function as well as its role in renal pathophysiology has been appreciated for decades; however, there still exist important gaps in knowledge in our understanding of the mechanistic pathways activated by this system in the kidney. The purpose of this article is to review recent advances in the field, as well as to underscore areas that need more investigation, with an emphasis on the interplay of ET-1 with inflammation, sex differences, circadian rhythms of renal function, the most recent clinical trials involving the ET-1 system, and the interaction between microRNAs and the ET-1 system.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F815-F827"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059578","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":"Lack of a role of NHE4 in renal ammonia metabolism.","authors":"Hyun-Wook Lee, Autumn N Harris, Kelly A Hyndman, I David Weiner","doi":"10.1152/ajprenal.00044.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00044.2025","url":null,"abstract":"<p><p>The cation exchanger, Na⁺/H⁺ exchanger isoform 4 (NHE4), has been thought to have a central role in renal ammonia metabolism and handling by acting in a Na⁺ for NH₄⁺ exchange mode at the basolateral plasma membrane in the thick ascending limb (TAL) of the loop of Henle. These studies aimed to determine the effect of NHE4 deletion on ammonia metabolism under basal conditions and in response to metabolic acidosis. Constitutive NHE4 deletion resulted in increased urine ammonia excretion associated with significantly lower urine pH; this increase did not lead to metabolic alkalosis. In response to exogenous acid-loading, NHE4 deletion did not impair the changes in ammonia excretion. Immunoblot analysis and immunohistochemistry showed mild increases in proximal tubule ammoniagenic enzyme expression with NHE4 deletion. Both immunoblot analysis and immunohistochemistry showed no detectable NHE4 protein expression in the mouse kidney. Single-nucleus RNAseq of mouse kidneys showed no NHE4 mRNA expression in renal epithelial cells. Analysis of five publicly available mouse and human cell-specific RNAseq datasets also showed a lack of NHE4 mRNA expression in the TAL. We conclude that NHE4 is unnecessary for ammonia metabolism either under basal conditions or in response to acid-loading because it is not expressed in the TAL.<b>NEW & NOTEWORTHY</b> NHE4 has previously been suggested to mediate a critical role in renal ammonia metabolism through its role in thick ascending limb (TAL) ammonia transport. This manuscript shows that its deletion does not alter renal ammonia handling and that neither the mouse nor human kidney expresses NHE4 in the TAL.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"328 6","pages":"F752-F765"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045935","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":"Deletion of the prostaglandin EP4 receptor in the kidney tubule of mature mice alters kidney water handling only in males.","authors":"Cristina Esteva-Font, Xiang Zheng, Crissy F Rudolphi, Toke P K Hansen, Ewout J Hoorn, Robert A Fenton","doi":"10.1152/ajprenal.00071.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00071.2025","url":null,"abstract":"<p><p>Prostaglandin E2 (PGE₂) is a lipid mediator modulating several aspects of kidney function. PGE₂ acts via four prostanoid receptors, EP1 to EP4. In renal tubules, EP4 has very low expression, yet a role for EP4 in maintaining water balance has been proposed. The major aim of this study was to clarify the role of the EP4 receptor in the kidney tubule of adult mice for body water homeostasis. To examine this, a mouse model with doxycycline-dependent deletion of EP4 along the renal tubule (Pax8Cre system) was developed and phenotyped with respect to water handling. Two weeks after doxycycline treatment, EP4 mRNA expression (RT-qPCR) was reduced by >80% in the medulla of male and female knockout mice (<i>EP4</i>^-/-) compared with controls (<i>EP4</i>^+/+). With free access to water, there were no detectable differences between genotypes in food intake, body weight, or plasma biochemistries. Male, but not female, <i>EP4</i>^-/- mice had a small but significantly higher basal urinary output with decreased osmolality, concomitant with lower urinary Na⁺, K⁺, Cl^-, urea, and creatinine concentrations. The urea channel UT-A1 was reduced in the medulla, but otherwise no major differences in the levels of proteins involved in water balance were observed between genotypes. There were no differences between genotypes in their ability to concentrate urine during a 14-h water restriction or after treatment with the vasopressin V2 receptor agonist 1-deamino-8-d-arginine-vasopressin. <i>EP4</i>^-/- mice of both sexes excreted an acute water load similarly to control mice. In conclusion, EP4 in the renal tubule has a mild role in renal water handling, but only in male mice. This new model provides a novel tool for assessing the role of EP4 in kidney tubule function in various (patho)physiological conditions independently of developmental abnormalities or systemic effects.<b>NEW & NOTEWORTHY</b> Acting through the EP1-EP4 receptors, prostaglandin E2 (PGE₂) modulates various aspects of kidney function. Despite extremely low expression in the collecting duct, EP4 has been proposed to play a key role in regulation of Aquaporin-2 and water balance. In this study, we show that EP4 only plays a mild role in kidney water handling in male mice, calling into question the standard concepts presented in physiology textbooks regarding PGE₂ actions on the collecting duct.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"328 6","pages":"F800-F814"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055371","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":"Kir4.1/Kir5.1 of distal convoluted tubule is required for short-term angiotensin-II-induced stimulation of Na-Cl cotransporter.","authors":"Xin-Peng Duan, Xin-Xin Meng, Yu Xiao, Cheng-Biao Zhang, Ruimin Gu, Dao-Hong Lin, Wen-Hui Wang","doi":"10.1152/ajprenal.00004.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00004.2025","url":null,"abstract":"<p><p>Angiotensin-II (Ang-II) perfusion stimulates inwardly-rectifying potassium channels 4.1 and 5.1 (Kir4.1/Kir5.1) in distal convoluted tubule (DCT) and thiazide-sensitive Na-Cl cotransporter (NCC). The aim of the present study is to explore the role of Kir4.1/Kir5.1 in mediating the effect of Ang-II on NCC. We used immunoblotting and patch-clamp experiments to examine the effect of 1- or 7-day Ang-II perfusion on basolateral Kir4.1/Kir5.1 in the DCT and NCC using kidney-tubule-specific (Ks) angiotensin II type 1a receptor (AT1Ar)-knockout (KO), Ks-Kir4.1-knockout and the corresponding wild-type mice. Ang-II perfusion for 1 and 7 days increased phospho-NCC (pNCC) and total-NCC (tNCC) expression and the effect of Ang-II perfusion on pNCC and tNCC was abolished in Ks-AT1aR-KO. Ang-II perfusion for 1 day robustly stimulates Kir4.1/Kir5.1 in the late DCT (DCT2) and to a lesser degree in the early DCT (DCT1), an effect was absent in Ks-AT1aR-KO mice. However, Ang-II perfusion for 7 days did not further stimulate Kir4.1/Kir5.1 in the DCT2 and only modestly increased Kir4.1/Kir5.1-mediated K⁺ currents in DCT1. Deletion of Kir4.1 not only significantly decreased the expression of pNCC and tNCC, but also abolished the effect of 1-day Ang-II perfusion on the expression of phospho-with-no-lysine kinase-4 (pWNK4), phospho-ste-20-proline-alanine-rich kinase (pSPAK), Pncc, and tNCC. However, 7-day Ang-II perfusion was still able to significantly stimulate the expression of pSPAK, pWNK4, pNCC, and tNCC, and increased thiazide-induced natriuresis in Ks-Kir4.1-KO mice without obvious changes in K⁺ channel activity in the DCT. We conclude that short-term Ang-II-induced stimulation of pWNK4, pSPAK, and pNCC depends on Kir4.1/Kir5.1 activity. However, long-term Ang-II is able to directly stimulate pWNK4, pSPAK, and pNCC by a Kir4.1/Kir5.1 independent mechanism.<b>NEW & NOTEWORTHY</b> We investigated the role of Kir4.1/Kir5.1 in mediating the effect of short-term Ang-II on Na-Cl cotransporter (NCC) expression/activity. We demonstrated that Kir4.1/Kir5.1 in the distal convoluted tubule is required for short-term Ang-II-induced stimulation of with-no-lysine-kinase 4 (WNK4), ste20-proline-alanine-rich kinase (SPAK), and NCC. However, sustained Ang-II stimulation is expected to activate WNK4, SPAK, and NCC by Kir4.1/Kir5.1-independent mechanism.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"328 6","pages":"F775-F786"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054948","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 knock-out of paracingulin attenuates hypertension through modulation of kidney ion transport.","authors":"Florian Rouaud, Merlijn J Meens, Raphaël Yvon, Aurélie Hautefort, David Legouis, Isabelle Mean, Lionel Jond, Marc Maillard, Brenda R Kwak, Solange Moll, Sophie De Seigneux, Eric Feraille, Sandra Citi","doi":"10.1152/ajprenal.00271.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00271.2024","url":null,"abstract":"<p><p>Hypertension is a major risk factor for human morbidity and mortality, and the junctional protein paracingulin (CGNL1, JACOP) is required for the development of hypertension in a Dahl salt-sensitive rat model and is linked to human hypertension in genome wide association studies. However, the mechanism through which CGNL1 may regulate hypertension is unknown. Here, we address this question using a mouse model, where hypertension is induced by unilateral nephrectomy and angiotensin II infusion (N+A protocol). Although untreated WT and CGNL1-KO mice showed similar blood pressure, the N+A protocol induced hypertension in WT mice but not in CGNL1-KO mice. We show by immunolocalization and transcriptomic analysis that CGNL1 is expressed throughout the kidney tubules and in the endothelium of blood vessels, but not in smooth muscle. The N+A protocol induced decreased potassium urinary excretion in wild-type (WT), but not in CGNL1-KO mice. Immunoblot analysis shows that the KO of CGNL1 blunted the N+A-induced changes in the expression levels and activation of tubular ion transporters, including the Na/H exchanger 3 (NHE3) and the thiazide-sensitive Na-Cl cotransporter (NCC), and blunted the angiotensin II-dependent changes in the levels and/or activation of AMP-activated protein kinase (AMPK), ERK and myosin light chain. In contrast, myography showed comparable vascular reactivity in thoracic aortas and mesenteric arteries isolated from WT or CGNL1-KO mice. Together, these results suggest the KO of CGNL1 attenuates hypertension by uncoupling angiotensin II signaling in kidney tubule cells, indicating a novel pathway of regulation of signaling by a junctional protein.<b>NEW & NOTEWORTHY</b> The knock-out of paracingulin (CGNL1) prevents the development of hypertension in a unilateral nephrectomy/angiotensin II infusion model (N+A) in mice and this antihypertensive effect likely depends on uncoupling of angiotensin II from stimulation of sodium transporter activity in kidney tubules rather than on alteration of resistance blood vessel contractility.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"328 6","pages":"F737-F751"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065326","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":"Furin-mediated modification is required for epithelial sodium channel-activating activity of soluble (pro)renin receptor in cultured collecting duct cells.","authors":"Huaqing Zheng, My N Helms, Changjiang Zou, Elizabeth Zimmerman, Ye Feng, Tianxin Yang","doi":"10.1152/ajprenal.00087.2024","DOIUrl":"10.1152/ajprenal.00087.2024","url":null,"abstract":"<p><p>(Pro)renin receptor (PRR) contains an overlapping cleavage site for site-1 protease (S1P) and furin for the generation of soluble PRR (sPRR). Although S1P-mediated cleavage mediates the release of sPRR, the functional implication of furin-mediated cleavage is unclear. Here, we tested whether furin-mediated cleavage was required for the activity of sPRR in activating epithelial Na⁺ channel (ENaC) in cultured M-1 cells. M-1 cells were transfected with pcDNA3.4 containing full-length PRR with (Furin-site Mut) or without (WT) mutagenesis of the furin cleavage site. As compared with empty vector (EM) control, Furin-site Mut showed the attenuation effect on WT-induced α-ENaC expression and amiloride-sensitive short-circuit current. In a separate experiment, M-1 cells were transfected with pcDNA3.4 containing cDNA for sPRR with S1P cleavage (AA 1-282) (sPRR-S1P) or with furin cleavage (AA 1-279) (sPRR-furin), indicating overexpression of the two types of sPRR induced a significant and comparable increase in the release of sPRR, but only sPRR-furin showed an increase of ENaC activity. Single-channel analysis of ENaC activity in Xenopus A6-2F3 cells confirms sPRR-furin activation of ENaC open probability. At last, HEK-293 cells were pretreated with furin inhibitor α₁-antitrypsin Portland (α₁-PDX) followed by transfection with EM, WT PRR. sPRR in the conditioned medium was enriched by using protein centrifugal filter devices and applied to M-1 cells followed by measurement of ENaC activity, demonstrating that pretreatment with α₁-PDX attenuated ENaC-acting activity induced by overexpression of WT PRR. In summary, we conclude that furin-mediated modification is required for the activity of sPRR to increase ENaC-mediated Na⁺ transport in the collecting duct cells.<b>NEW & NOTEWORTHY</b> The present study for the first time examined the functional implication of furin-dependent cleavage in the activation of sPRR during ENaC regulation in cultured CD cells. We found that sPRR with the initial S1P-dependent cleavage remained silent and only became active following furin-dependent cleavage in terms of enhancement of ENaC activity and expression of α-ENaC. These results offer novel insight into the sPRR maturation process during ENaC regulation.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F766-F774"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054301","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":"https://doi.org/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 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 <i>in situ</i> hybridization. We report the transcriptional abundance of six AGPCRs that are expressed in a cell-specific manner, but also demonstrate that Adgrf1, a receptor with low but specific abundance by snRNAseq, is detected in a subset of principal cells by RNAscope. Additionally, we identify cell-specific transcript variants of Adgrf5 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.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","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":"Knockout of the V-ATPase interacting protein Tldc2 in B-type kidney intercalated cells impairs urine alkalinization.","authors":"Amity F Eaton, Elizabeth C Danielson, Leona J Tu, Dennis Brown, Maria Merkulova","doi":"10.1152/ajprenal.00363.2024","DOIUrl":"https://doi.org/10.1152/ajprenal.00363.2024","url":null,"abstract":"<p><p>Intercalated cells (ICs) are acid-base regulatory cells in the kidney collecting duct that excrete either acid or base into the urine in response to systemic cues. A-ICs deliver protons into the tubule lumen via an apical proton pump (V-ATPase) and reabsorb base (bicarbonate) using the AE1 anion exchanger. B-ICs function in the opposite direction. They have basolateral V-ATPase and secrete bicarbonate into the lumen via the anion exchange protein, pendrin. The function of a third IC subtype, the non-A non-B IC which has apical pendrin and apical V-ATPase, is less well understood. We previously reported that members of the TLDc protein family interact with the V-ATPase and may regulate its function. TLDc proteins exhibit a distinct expression pattern in the kidney with RNAseq showing high, differential expression of Tldc2 in B-ICs. Here, we show by RNAscope imaging that Tldc2 is indeed expressed in B-ICs, but also in some non-A, non-B ICs. Using <i>Tldc2</i> knockout (<i>Tldc2^-/-</i>) mice, we found that males and females had significantly lower urine pH than wild-type littermates, and their ability to increase urine pH in response to a bicarbonate load was impaired. In addition, <i>Tldc2^-/-</i> males developed hyperbicarbonatemia. <i>Tldc2^-/-</i> kidneys contained fewer B-ICs than wild-type mice, but they were replaced by more non-A, non-B ICs; the number of A-ICs was unchanged. Finally, there was decreased basolateral accumulation of V-ATPase in <i>Tldc2^-/-</i> B-ICs. These findings suggest that <i>Tldc2</i> is a novel gene involved in renal acid-base regulation and in addition, may serve as a differentiation marker for B-ICs.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002037","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}