American journal of physiology. Renal physiology最新文献

{"title":"Lack of renoprotective effects by long-term PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin in obese ZSF1 rats.","authors":"Sandra Hummelgaard, Henning Hvid, Henrik Birn, Simon Glerup, Nikola Tom, Mesut Bilgin, Jeppe Egedal Kirchhoff, Kathrin Weyer","doi":"10.1152/ajprenal.00065.2024","DOIUrl":"10.1152/ajprenal.00065.2024","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). Despite the entry of sodium glucose cotransporter 2 (SGLT2) inhibitors, CKD persists as a medical challenge. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces low-density lipoprotein (LDL)-cholesterol, a major risk factor of CVD. Interestingly, studies indicate that PCSK9 inhibition decreases proteinuria in kidney disease, complementing the reduced CVD risk. This study aimed to validate obese ZSF1 rats as a model for the renoprotective effects of PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin for 15 wk. Obese rats revealed a significant reduction in measured glomerular filtration rate (mGFR) and increased urine albumin/creatinine ratio (UACR) during follow-up compared with lean controls. Alirocumab treatment resulted in a decline in mGFR and increased UACR compared with vehicle-treated obese rats. Immunohistochemistry showed increased fibrosis and inflammation in kidney tissue from obese rats treated with empagliflozin or alirocumab, whereas hepatic cholesterol and triglyceride levels were lowered compared with vehicle-treated obese rats. Although alirocumab lowered circulating free cholesterol levels throughout the treatment period, certain cholesteryl esters were increased at the end of the study, resulting in no overall difference in total cholesterol levels in the alirocumab group. Correspondingly, only a trend toward increased hepatic LDL-receptor levels was observed. In conclusion, these findings suggest that alirocumab treatment aggravates kidney dysfunction in obese ZSF1 rats. Moreover, in contrast to the renoprotective properties of empagliflozin observed in patients with CKD, empagliflozin did not ameliorate kidney disease progression in the obese ZSF1 rat.<b>NEW & NOTEWORTHY</b> New treatments to slow kidney disease progression and reduce cardiovascular disease risk are needed for chronic kidney disease (CKD). We investigated the cholesterol-lowering PCSK9 inhibitor alirocumab as a new treatment for proteinuric CKD and the effect of SGLT2 inhibition using empagliflozin in obese ZSF1 rats. Regarding renoprotection, our findings were contradictory with previous preclinical studies and clinical data, suggesting that different pathophysiological mechanisms may apply to this rat model.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F48-F67"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649940","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":"Phosphoproteomic response to epidermal growth factor in native rat inner medullary collecting duct.","authors":"Chung-Lin Chou, Nipun U Jayatissa, Elena T Kichula, Shuo-Ming Ou, Kavee Limbutara, Mark A Knepper","doi":"10.1152/ajprenal.00182.2024","DOIUrl":"10.1152/ajprenal.00182.2024","url":null,"abstract":"<p><p>Epidermal growth factor (EGF) has important effects in the renal collecting duct to regulate salt and water transport. To identify elements of EGF-mediated signaling in the rat renal inner medullary collecting duct (IMCD), we carried out phosphoproteomic analysis. Biochemically isolated rat IMCD suspensions were treated with 1 µM of EGF or vehicle for 30 min. We performed comprehensive quantitative phosphoproteomics using tandem mass tag (TMT)-labeling of tryptic peptides followed by protein mass spectrometry. We present a data resource reporting all detected phosphorylation sites and their changes in response to EGF. For a total of 29,881 unique phosphorylation sites, 135 sites were increased and 119 sites were decreased based on stringent statistical analysis. The data are provided to users at https://esbl.nhlbi.nih.gov/Databases/EGF-phospho/. The analysis demonstrated that EGF signals through canonical EGF pathways in the renal IMCD. Analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in which EGF-regulated phosphoproteins are over-represented in native rat IMCD cells confirmed mapping to RAF-MEK-extracellular signal-regulated kinase (ERK) signaling but also pointed to a role for EGF in the regulation of protein translation. A large number of phosphoproteins regulated by EGF contained PDZ domains that are key elements of epithelial polarity determination. We also provide a collecting duct EGF-network map as a user-accessible web resource at https://esbl.nhlbi.nih.gov/Databases/EGF-network/. Overall, the phosphoproteomic data presented provide a useful resource for experimental design and modeling of signaling in the renal collecting duct.<b>NEW & NOTEWORTHY</b> EGF negatively regulates transepithelial water and salt transport across the kidney collecting duct. This study identified phosphoproteins affected by EGF stimulation in normal rat collecting ducts, providing insights into global cell signaling mechanisms. Bioinformatic analyses highlighted enhanced canonical ERK signaling alongside a diminished activity in the PI3K-Akt pathway, which is crucial for cell proliferation and survival. This EGF response differs somewhat from prior studies where both pathways were prominently activated.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F29-F47"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604545","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":"Transcriptomics of SGLT2-positive early proximal tubule segments in mice: response to type 1 diabetes, SGLT1/2 inhibition, or GLP1 receptor agonism.","authors":"Young Chul Kim, Vivek Das, Sadhana Kanoo, Huazhen Yao, Stephanie M Stanford, Nunzio Bottini, Anil Karihaloo, Volker Vallon","doi":"10.1152/ajprenal.00231.2024","DOIUrl":"10.1152/ajprenal.00231.2024","url":null,"abstract":"<p><p>SGLT2 inhibitors (SGLT2i) and GLP1 receptor (GLP1R) agonists have kidney protective effects. To better understand their molecular effects, RNA sequencing was performed in SGLT2-positive proximal tubule segments isolated by immunostaining-guided laser capture microdissection. Male adult DBA wild-type (WT) and littermate diabetic Akita mice ± <i>Sglt1</i> knockout (<i>Sglt1</i>-KO) were given vehicle or SGLT2i dapagliflozin (dapa; 10 mg/kg diet) for 2 wk, and other Akita mice received GLP1R agonist semaglutide [sema; 3 nmol/(kg body wt·day), sc]. Dapa (254 ± 11 mg/dL) and <i>Sglt1</i>-KO (367 ± 11 mg/dL) but not sema (407 ± 44 mg/dL) significantly reduced hyperglycemia in Akita mice (480 ± 33 mg/dL). The 20,748 detected annotated protein-coding genes included robust enrichment of S1-segment marker genes. Akita showed 198 (∼1%) differentially expressed genes versus WT (DEGs; adjusted <i>P</i> ≤ 0.1), including downregulation of anionic transport, unsaturated fatty acid, and carboxylic acid metabolism. Dapa changed only two genes in WT but restored 43% of DEGs in Akita, including upregulation of the lipid metabolic pathway, carboxylic acid metabolism, and organic anion transport. In Akita, sema restored ∼10% of DEGs, and <i>Sglt1</i>-KO and dapa were synergistic (restored ∼61%), possibly involving additive blood glucose effects (193 ± 15 mg/dL). Targeted analysis of transporters and channels (<i>t</i> test, <i>P</i> < 0.05) revealed that ∼10% of 526 detectable transporters and channels were downregulated by Akita, with ∼60% restored by dapa. Dapa, dapa + <i>Sglt1</i>-KO, and sema also altered Akita-insensitive genes. Among DEGs in Akita, ∼30% were unresponsive to any treatment, indicating potential new targets. In conclusion, SGLT2i restored transcription for multiple metabolic pathways and transporters in SGLT2-positive proximal tubule segments in diabetic mice, with a smaller effect also observed for GLP1R agonism.<b>NEW & NOTEWORTHY</b> SGLT2 inhibitors and GLP1 receptor agonists have kidney protective effects. By combining immunostaining-guided laser capture microdissection and RNA sequencing, the study established how the gene expression profile changes in SGLT2-positive proximal tubule cells in response to type 1 Akita diabetes and to pharmacological intervention by SGLT2 inhibition or GLP1R agonism and genetic deletion of SGLT1. The data also indicate genes unresponsive to those treatments that may include new therapeutical candidates.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F68-F81"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717879","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 brief history of the cortical thick ascending limb: a systems-biology perspective.","authors":"Shahzad K Sohail, Nipun U Jayatissa, Raymond Mejia, Shaza Khan, Chung-Lin Chou, Chin-Rang Yang, Mark A Knepper","doi":"10.1152/ajprenal.00243.2024","DOIUrl":"10.1152/ajprenal.00243.2024","url":null,"abstract":"<p><p>Here, we review key events in the accrual of knowledge about the cortical thick ascending limb (CTAL) of the kidney, starting with its initial characterization by Maurice Burg in 1973. Burg's work showed that the CTAL actively reabsorbs NaCl and that, because its water permeability is virtually zero, it can lower the luminal NaCl concentration to a \"static head\" level well below blood levels. This process is central to the kidney's ability to excrete dilute urine in states of high water intake. Following Burg's original observations, Greger and Schlatter, working in the 1980s, identified the membrane transport processes responsible for transepithelial NaCl transport in the CTAL. In the 1990s, several investigators identified the key transporter genes and proteins at a molecular level by cDNA cloning. The successful completion of human and mouse genome sequencing projects at the turn of the century led to the development of transcriptomic and proteomic methodologies that allowed the identification of complete transcriptomes and proteomes of CTAL cells. Knowledge accrual was enhanced by the development of differential equation-based models of transport in the CTAL in the 2010s. Here, we used a simplified mathematical model of NaCl (\"salt\"), urea, and water transport in the CTAL to address three key questions about CTAL function: <i>1</i>) What is the mechanism of Burg's \"static head\" phenomenon? <i>2</i>) How does the kidney compensate for the very short length of the CTALs of juxtamedullary nephrons? <i>3</i>) Which of the three isoforms of the apical Na-K-2Cl cotransporter (NKCC2) dominates functionally in the CTAL?<b>NEW & NOTEWORTHY</b> Here, we review key events in the accrual of knowledge about the cortical thick ascending limb (CTAL) of the kidney, starting with its initial characterization by Maurice Burg in 1973, and culminating with the application of systems biology techniques including mathematical modeling.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F82-F94"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670078","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":"Tcf21 as a founder transcription factor in specifying Foxd1 cells to the juxtaglomerular cell lineage.","authors":"Hina Anjum, Jason P Smith, Alexandre G Martini, George S Yacu, Silvia Medrano, R Ariel Gomez, Maria Luisa S Sequeira-Lopez, Susan E Quaggin, Gal Finer","doi":"10.1152/ajprenal.00235.2024","DOIUrl":"10.1152/ajprenal.00235.2024","url":null,"abstract":"<p><p>Renin is crucial for blood pressure regulation and electrolyte balance, and its expressing cells arise from Forkhead box D1-positive (Foxd1⁺) stromal progenitors. However, factors guiding these progenitors toward renin-secreting cell fate remain unclear. Tcf21, a basic helix-loop-helix (bHLH) transcription factor, is essential in kidney development. Using <i>Foxd1^Cre/+;Tcf21^f/f</i> and <i>Ren1^dCre/+;Tcf21^f/f</i> mouse models, we investigated the role of Tcf21 in the differentiation of Foxd1⁺ progenitor cells into juxtaglomerular (JG) cells. Immunostaining and in situ hybridization demonstrated fewer renin-positive areas and altered renal arterial morphology, including the afferent arteriole, in <i>Foxd1^Cre/+;Tcf21^f/f</i> kidneys compared with controls, indicating Tcf21's critical role in the emergence of renin-expressing cells. However, Tcf21 inactivation in renin-expressing cells (<i>Ren1^dCre/+;Tcf21^f/f</i>) did not recapitulate this phenotype, suggesting Tcf21 is dispensable once renin cell identity is established. Using an integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on GFP⁺ cells (stromal lineage) from E12, E18, P5, and P30 <i>Foxd1^Cre/+;Rosa26^mTmG</i> control kidneys, we analyzed the temporal dynamics of Tcf21 expression in cells comprising the JG lineage (<i>n</i> = 2,054). A pseudotime trajectory analysis revealed that Tcf21 expression is highest in metanephric mesenchyme and stromal cells at early developmental stages (E12), with a decline in expression as cells mature into renin-expressing JG cells. Motif enrichment analyses supported Tcf21's significant involvement in early kidney development. These findings underscore the critical role of Tcf21 in Foxd1⁺ cell differentiation into JG cells during early stages of kidney development, offering insights into the molecular mechanisms governing JG cell differentiation and highlighting Tcf21's pivotal role in kidney development.<b>NEW & NOTEWORTHY</b> This manuscript provides novel insights into the role of Tcf21 in the differentiation of Foxd1⁺ cells into JG cells. Using integrated scRNA-seq and scATAC-seq, the study reveals that Tcf21 expression is crucial during early embryonic stages, with its peak at <i>embryonic day 12.</i> The findings demonstrate that inactivation of Tcf21 leads to fewer renin-positive areas and altered renal arterial morphology, underscoring the importance of Tcf21 in the specification of renin-expressing JG cells and kidney development.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F121-F130"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717876","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":"Sex differences in the adrenal circadian clock: a role for BMAL1 in the regulation of urinary aldosterone excretion and renal electrolyte balance in mice.","authors":"Hannah M Costello, Sophia A Eikenberry, Kit-Yan Cheng, Bryanna Broderick, Advay S Joshi, Gianna R Scott, Annalisse McKee, Victor M Mendez, Lauren G Douma, G Ryan Crislip, Michelle L Gumz","doi":"10.1152/ajprenal.00177.2024","DOIUrl":"10.1152/ajprenal.00177.2024","url":null,"abstract":"<p><p>Brain and muscle ARNT-Like 1 (BMAL1) is a circadian clock transcription factor that regulates physiological functions. Male adrenal-specific <i>Bmal1</i> (<i>AS^Cre/+::Bmal1</i>) KO mice displayed blunted serum corticosterone rhythms, altered blood pressure rhythm, and altered timing of eating, but there is a lack of knowledge in females. This study investigates the role of adrenal BMAL1 in renal electrolyte handling and urinary aldosterone levels in response to low salt in male and female mice. Mice were placed in metabolic cages to measure 12-h urinary aldosterone after a standard diet and 7 days low-salt diet, as well as daily body weight, 12-h food and water intake, and renal sodium and potassium balance. Adrenal glands and kidneys were collected at ZT0 or ZT12 to measure the expression of aldosterone synthesis genes and clock genes. Compared with littermate controls, <i>AS^Cre/+::Bmal1</i> KO male and female mice displayed increased urinary aldosterone in response to a low-salt diet, although mRNA expression of aldosterone synthesis genes was decreased. Timing of food intake was altered in <i>AS^Cre/+::Bmal1</i> KO male and female mice, with a blunted night/day ratio. <i>AS^Cre/+::Bmal1</i> KO female mice displayed decreases in renal sodium excretion in response to low salt, but both male and female KO mice had changes in sodium balance that were time-of-day-dependent. In addition, sex differences were found in adrenal and kidney clock gene expression. Notably, this study highlights sex differences in clock gene expression that could contribute to sex differences in physiological functions.<b>NEW & NOTEWORTHY</b> Our findings highlight the importance of sex as well as time-of-day in understanding the role of the circadian clock in the regulation of homeostasis. Time-of-day is a key biological variable that is often ignored in research, particularly in preclinical rodent studies. Our findings demonstrate important differences in several measures at 6 AM compared with 6 PM. Consideration of time-of-day is critical for the translation of findings in nocturnal rodent physiology to diurnal human physiology.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1-F14"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514473","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":"Expression and distribution of MUC1 in the developing and adult kidney.","authors":"Carlos L Manrique-Caballero, Jonathan Barasch, Syed K Zaidi, Carlton M Bates, Evan C Ray, Thomas R Kleyman, Mohammad M Al-Bataineh","doi":"10.1152/ajprenal.00206.2024","DOIUrl":"10.1152/ajprenal.00206.2024","url":null,"abstract":"<p><p>Mucin 1 (or MUC1) is a heterodimeric transmembrane glycoprotein expressed on the apical surface of polarized epithelial cells in several tissues including the kidney. Recent studies have revealed several novel roles of MUC1 in the kidney, potentially including bacterial infection, mineral balance, and genetic interstitial kidney disease, even though MUC1 levels are reduced not only in the kidney but also in all tissues due to MUC1 mutations. A careful localization of MUC1 in discrete segments of the nephron is the first step in understanding the multiple functional roles of MUC1 in the kidney. Most published reports of MUC1 expression to date have been largely confined to cultured cells, tumor tissues, and selective nephron segments of experimental rodents, and very few studies have been performed using human kidney tissues. Given the rising attention to the role of MUC1 in differing components of renal physiology, we carefully examined the kidney distribution of MUC1 in both human and mouse kidney sections using well-defined markers for different nephron segments or cell types. We further extended our investigation to include sections of early stages of mouse kidney development and upon injury in humans. We included staining for MUC1 in urothelial cells, the highly specialized epithelial cells lining the renal pelvis and bladder. These data implicate a role for MUC1 in antimicrobial defense. Our study provides the groundwork to test the physiological relevance of MUC1 in the urinary tract.<b>NEW & NOTEWORTHY</b> MUC1 is a transmembrane glycoprotein expressed on the apical surface of polarized epithelial tissues and most carcinomas. MUC1 may play novel roles in the kidney including defense against infections. Here, we examine the expression of MUC1 in mouse and human kidneys. We show that the distal nephron and the urinary system are the predominant sites of expression of both message and protein, implicating segment-specific roles including distal nephron defense against ascending bacteria.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F107-F120"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717872","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":"Exosomes derived from TREM-2 knocked-out macrophages alleviated renal fibrosis via HSPa1b/AKT pathway.","authors":"Zihao Xiao, Yajie Wang, Yuye Chen, Ling Jin, Yuanhui Shi, Can Liu, Cong Fu, Yuhan Cao","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Macrophages are recognized as vital players in renal fibrosis, with a high degree of heterogeneity and plasticity, and the triggering receptor expressed on myeloid cell-2 (TREM-2) is highly expressed on macrophages and participates in the progression of tissue fibrosis. However, the mechanism by which TREM-2 mediates the progression of renal fibrosis is still unclear. Our study revealed that exosomes derived from TREM-2-deficient (TREM-2^-/-) macrophages suppressed the progression of fibrosis, as indicated by a greater matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) ratio at the protein level in secreted exosomes than in exosomes from wild-type (WT) macrophages in the fibrotic microenvironment. In addition, renal tubular epithelial cells (TECs) engulfed these nanoscale vesicles, and the expression of collagen I and α-smooth muscle actin (α-SMA) (a fibrosis-related marker) was obviously decreased. Through RNA-seq, we found that TREM-2^-/- macrophages increase the MMP-9/TIMP-1 ratio in their exosomes via the HSPa1b/AKT pathway. Notably, renal fibrosis was effectively alleviated in the obstructed kidneys of mice that received a renal pelvis injection of an adeno-associated virus (AAV-shTREM-2) containing the sequence used to silence TREM-2. However, VER-155008 (an inhibitor of HSPa1b) and Ly294002 (an inhibitor of AKT) reversed this effect. Moreover, polyclonal antibodies against TREM-2 also effectively relieved UUO-induced renal fibrosis. Overall, we validated that knocking down TREM-2 expression can inhibit the progression of renal fibrosis through a macrophage exosome-dependent pathway both in vitro and in vivo. Hence, our findings suggest that TREM-2 is a potential therapeutic target for CKD.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"None"},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831192","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 AT_1a receptors selectively in the proximal tubules of the kidney alters the hypotensive and natriuretic response to atrial natriuretic peptide via NPR_A/cGMP/NO signaling.","authors":"Xiao Chun Li, Chih-Hong Wang, Rumana Hassan, Akemi Katsurada, Ryosuke Sato, Jia Long Zhuo","doi":"10.1152/ajprenal.00160.2024","DOIUrl":"10.1152/ajprenal.00160.2024","url":null,"abstract":"&lt;p&gt;&lt;p&gt;In the proximal tubules of the kidney, angiotensin II (ANG II) binds and activates ANG II type 1 (AT&lt;sub&gt;1a&lt;/sub&gt;) receptors to stimulate proximal tubule Na&lt;sup&gt;+&lt;/sup&gt; reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates natriuretic peptide receptors (NPR&lt;sub&gt;A&lt;/sub&gt;) to inhibit ANG II-induced proximal tubule Na&lt;sup&gt;+&lt;/sup&gt; reabsorption. These two vasoactive systems play important counteracting roles to control Na&lt;sup&gt;+&lt;/sup&gt; reabsorption in the proximal tubules and help maintain blood pressure homeostasis. However, how AT&lt;sub&gt;1a&lt;/sub&gt; and NPR&lt;sub&gt;A&lt;/sub&gt; receptors interact in the proximal tubules and whether natriuretic effects of NPR&lt;sub&gt;A&lt;/sub&gt; receptor activation by ANP may be potentiated by deletion of AT&lt;sub&gt;1&lt;/sub&gt; (AT&lt;sub&gt;1a&lt;/sub&gt;) receptors selectively in the proximal tubules have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT&lt;sub&gt;1a&lt;/sub&gt; receptors, PT-&lt;i&gt;Agtr1a&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt;, to test the hypothesis that deletion of AT&lt;sub&gt;1a&lt;/sub&gt; receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), fractional proximal tubule Na&lt;sup&gt;+&lt;/sup&gt; reabsorption was significantly lower (&lt;i&gt;P&lt;/i&gt; &lt; 0.05), whereas 24-h urinary Na&lt;sup&gt;+&lt;/sup&gt; excretion was significantly higher, in PT-&lt;i&gt;Agtr1a&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt; mice than in wild-type mice (&lt;i&gt;P&lt;/i&gt; &lt; 0.01). Infusion of ANP via osmotic minipump for 2 wk (0.5 mg/kg/day ip) further significantly decreased blood pressure and increased the natriuretic response in PT-&lt;i&gt;Agtr1a&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt; mice by inhibiting proximal tubule Na&lt;sup&gt;+&lt;/sup&gt; reabsorption compared with wild-type mice (&lt;i&gt;P&lt;/i&gt; &lt; 0.01). These augmented hypotensive and natriuretic responses to ANP in PT-&lt;i&gt;Agtr1a&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt; mice were associated with increased plasma and kidney cGMP levels (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), kidney cortical NPR&lt;sub&gt;A&lt;/sub&gt; and NPR&lt;sub&gt;C&lt;/sub&gt; mRNA expression (&lt;i&gt;P&lt;/i&gt; &lt; 0.05), endothelial nitric oxide (NO) synthase (eNOS) and phosphorylated eNOS proteins (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), and urinary NO excretion (&lt;i&gt;P&lt;/i&gt; &lt; 0.01). Taken together, the results of the present study provide further evidence for important physiological roles of intratubular ANG II/AT&lt;sub&gt;1a&lt;/sub&gt; and ANP/NPR&lt;sub&gt;A&lt;/sub&gt; signaling pathways in the proximal tubules to regulate proximal tubule Na&lt;sup&gt;+&lt;/sup&gt; reabsorption and maintain blood pressure homeostasis.&lt;b&gt;NEW & NOTEWORTHY&lt;/b&gt; This study used a mutant mouse model with proximal tubule-selective deletion of angiotensin II (ANG II) type 1 (AT&lt;sub&gt;1a&lt;/sub&gt;) receptors to study, for the first time, important interactions between ANG II/AT&lt;sub&gt;1&lt;/sub&gt; (AT&lt;sub&gt;1a&lt;/sub&gt;) receptor/Na&lt;sup&gt;+&lt;/sup&gt;/H&lt;sup&gt;+&lt;/sup&gt; exchanger 3 and atrial natriuretic peptide (ANP)/natriuretic peptide receptor (NPR&lt;sub&gt;A&lt;/sub&gt;)/cGMP/nitric oxide signaling pathways in the proximal tubules. The results of the present study provide f","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F946-F956"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The FSGS protein actinin-4 interacts with NKCC2 to regulate thick ascending limb NaCl reabsorption.","authors":"Dipak Maskey, Tang-Dong Liao, D'Anna L Potter, Pablo A Ortiz","doi":"10.1152/ajprenal.00119.2024","DOIUrl":"10.1152/ajprenal.00119.2024","url":null,"abstract":"<p><p>In the kidney, the thick ascending limb (TAL) of the loop of Henle plays a vital role in NaCl homeostasis and blood pressure regulation. In human and animal models of salt-sensitive hypertension, NaCl reabsorption via the apical Na⁺/K⁺/2Cl^- cotransporter (NKCC2) is abnormally increased in the TAL. We showed that NaCl reabsorption is controlled by the presence of NKCC2 at the apical surface of TALs. However, the molecular mechanisms that maintain the steady-state levels of NKCC2 at the apical surface are not clearly understood. Here, we report that NKCC2 interacts with the F-actin cross-linking protein actinin-4 (ACTN4). We find that ACTN4 is expressed in TALs by Western blot and immunofluorescence microscopy. ACTN4 immunoprecipitated with NKCC2 and recombinant glutathione-<i>S</i>-transferase (GST)-ACTN4 pulled down NKCC2 from TAL lysates. ACTN4 is involved in endocytosis in other cells. Therefore, we hypothesized that ACTN4 binds apical NKCC2 and regulates its trafficking. To study the role of ACTN4 in NKCC2 surface expression, we silenced ACTN4 in vivo via shRNA or CRISPR/Cas9 system to decrease ACTN4 expression in TALs. We observed that silencing ACTN4 in vivo via shRNA or CRISPR/Cas9 system increased the amount of NKCC2 at the apical surface of TALs. Consistent with an increase in surface NKCC2, bumetanide-induced diuresis and natriuresis were enhanced by 35% after silencing of ACTN4 in vivo (AV-NKCC2-Cas9: 3,841 ± 709 vs. AAV-gRNA-ACTN4: 5,546 ± 622 µmol Na/8 h, <i>n</i> = 5, <i>P</i> < 0.05). We conclude that ACTN4 binds NKCC2 to regulate its surface expression. Selective depletion of ACTN4 in TALs using shRNA or CRISPR/Cas9 enhances surface NKCC2 and TAL-NaCl reabsorption, indicating that regulation of the ACTN4-NKCC2 interaction is important for renal NaCl reabsorption and could be related to hypertension.<b>NEW & NOTEWORTHY</b> ACTN4 function and dysfunction in glomerular podocytes have been extensively studied. However, the function of ACTN4 in the nephron has not been studied. Our paper shows for the first time that ACTN4, in the nephron, regulates NaCl reabsorption in part by affecting NKCC2 surface expression. Protein-protein interactions between ACTN4 and NKCC2 seem to mediate NKCC2 endocytosis in TALs. When ACTN4 was silenced in the TAL in vivo using CRISPR/Cas9 or shRNAs, surface NKCC2 and NaCl reabsorption increased.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1026-F1036"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514474","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}