American journal of physiology. Renal physiology最新文献

{"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717872","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":"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}

{"title":"Pathogenesis of HIV-associated nephropathy in children and adolescents: taking a hard look 40 years later in the era of gene-environment interactions.","authors":"Patricio E Ray, Jinliang Li, Jharna Das, Lian Xu, Jing Yu, Zhe Han","doi":"10.1152/ajprenal.00208.2024","DOIUrl":"10.1152/ajprenal.00208.2024","url":null,"abstract":"<p><p>HIV-associated nephropathy (HIVAN) is a kidney disease that affects mainly people of African ancestry with a high HIV-1 viral load. New antiretroviral therapies (ART) have been highly efficient in preventing and improving the outcome of HIVAN. However, providing chronic ART to children and adolescents living with HIV (CALWH) remains a significant challenge all over the world. More than 2.5 million CALWH, including those living in Sub-Saharan Africa, continue to be at high risk of developing HIVAN. Much of our understanding of the pathogenesis of HIVAN is based on studies conducted in transgenic mice and adults with HIVAN. However, CALWH may experience different health outcomes, risk factors, and susceptibilities to HIVAN in comparison to adults. This article reviews the progress made over the last 40 years in understanding the pathogenesis of HIVAN in CALWH, focusing on how the HIV virus, alongside genetic and environmental factors, contributes to the development of this disease. The landmark discovery that two risk alleles of the apolipoprotein-1 (APOL1) gene play a critical role in HIVAN has significantly advanced our understanding of the disease's pathogenesis. However, we still need to understand why renal inflammation persists despite ART and determine whether the kidney may harbor HIV reservoirs that need to be eliminated to cure HIV permanently. For these reasons, we emphasize reviewing how HIV-1 infects renal cells, affects their growth and regeneration, and discussing how inflammatory cytokines and APOL1 affect the outcome of childhood HIVAN.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1049-F1066"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334171","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":"First Author Highlights.","authors":"","doi":"10.1152/ajprenal.2024.327.6.AU","DOIUrl":"https://doi.org/10.1152/ajprenal.2024.327.6.AU","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":"327 6","pages":"i"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866590","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 central nervous system leptin administration attenuates kidney dysfunction and injury in a model of ischemia/reperfusion-induced acute kidney injury.","authors":"Jussara M do Carmo, John E Hall, Luzia N S Furukawa, Viktoria Woronik, Xuemei Dai, Emily Ladnier, Zhen Wang, Ana C M Omoto, Alan Mouton, Xuan Li, Emilio M Luna-Suarez, Alexandre A da Silva","doi":"10.1152/ajprenal.00158.2024","DOIUrl":"10.1152/ajprenal.00158.2024","url":null,"abstract":"<p><p>In the present study, we examined whether chronic intracerebroventricular (ICV) leptin administration protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Twelve-week-old male rats were implanted with an ICV cannula into the right lateral ventricle, and 8-10 days after surgery, leptin (0.021 µg/h, <i>n</i> = 8) or saline vehicle (0.5 µL/h, <i>n</i> = 8) was infused via osmotic minipump connected to the ICV cannula for 12 days. On <i>day 8</i> of leptin or vehicle infusion, rats were submitted to unilateral ischemia/reperfusion (UIR) by clamping the left pedicle for 30 min. To control for leptin-induced reductions in food intake, the vehicle-treated group was pair-fed (UIR-PF) to match the same amount of food consumed by leptin-treated (UIR-Leptin) rats. On the 12th day of leptin or vehicle infusion (fourth day after AKI), single-left kidney glomerular filtration rate (GFR) was measured, blood samples were collected to quantify white blood cells, and kidneys were collected for histological assessment of injury. UIR-Leptin-treated rats showed reduced right and left kidney weights (right: 1,040 ± 24 vs. 1,281 ± 36 mg; left: 1,127 ± 71 vs. 1,707 ± 45 mg, for UIR-Leptin and UIR-PF, respectively). ICV leptin infusion improved GFR (0.50 ± 0.06 vs. 0.13 ± 0.03 mL/min/g kidney wt) and reduced kidney injury scores. ICV leptin treatment also attenuated the reduction in circulating adiponectin levels that was observed in UIR-PF rats and increased the circulating white blood cells count compared with UIR-PF rats (16.3 ± 1.3 vs. 9.8 ± 0.6 k/µL). Therefore, we show that leptin, via its actions on the central nervous system, confers significant protection against major kidney dysfunction and injury in a model of ischemia/reperfusion-induced AKI.<b>NEW & NOTEWORTHY</b> A major new finding of this study is that chronic activation of leptin receptors in the CNS markedly attenuates acute kidney injury and protects against severe renal dysfunction after ischemia/reperfusion, independently of leptin's anorexic effects.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F957-F966"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373700","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":"Matrix metalloproteinases in kidney homeostasis and diseases: an update.","authors":"Roderick J Tan, Youhua Liu","doi":"10.1152/ajprenal.00179.2024","DOIUrl":"10.1152/ajprenal.00179.2024","url":null,"abstract":"<p><p>Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with important roles in kidney homeostasis and pathology. While capable of collectively degrading each component of the extracellular matrix, MMPs also degrade nonmatrix substrates to regulate inflammation, epithelial plasticity, proliferation, apoptosis, and angiogenesis. More recently, intriguing mechanisms that directly alter podocyte biology have been described. There is now irrefutable evidence for MMP dysregulation in many types of kidney disease including acute kidney injury, diabetic and hypertensive nephropathy, polycystic kidney disease, and Alport syndrome. This updated review will detail the complex biology of MMPs in kidney disease.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F967-F984"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373702","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":"Axial heterogeneity of superficial proximal tubule paracellular transport in mice.","authors":"Shigeaki Muto, Kazumasa Moriwaki, Daisuke Nagata, Mikio Furuse","doi":"10.1152/ajprenal.00187.2024","DOIUrl":"10.1152/ajprenal.00187.2024","url":null,"abstract":"<p><p>A considerable amount of NaCl reabsorption in proximal tubules (PTs) occurs via the paracellular transport regulated by the tight junction proteins claudins (Cldns). However, the paracellular transport properties in mouse superficial PTs remain unclear. We characterized these properties in superficial PT S1-S3 segments from mice expressing [wild-type (WT, WTS1-WTS3)] or lacking [knockout (KO, KOS1-KOS3)] claudin-2. We isolated and perfused segments with symmetrical solutions in the presence of bath ouabain and measured the diffusion potential upon changing the salt composition of the lumen or bath. Based on the diffusion potential corrected for the liquid junction potential (d<i>V</i>_T), we calculated the paracellular Na⁺ over Cl^- permeability (<i>P</i>_Na/<i>P</i>_Cl) ratio. The <i>P</i>_Na/<i>P</i>_Cl values upon reducing luminal NaCl averaged 1.27, 1.04, and 0.85 in WTS1, WTS2, and WTS3 and 0.34, 0.55, and 0.80 in KOS1, KOS2, and KOS3, respectively. The d<i>V</i>_T values exhibited a symmetrical response to bidirectional NaCl concentration gradients in WTS1-WTS3 and KOS1-KOS3. WTS1 and WTS3 were monovalent cation-selective, with WTS1 demonstrating stronger cation selectivity. The order of permeabilities relative to Cl^- was K⁺ > Rb⁺ > Na⁺ > Li⁺, whereas both KOS1 and KOS3 exhibited monovalent cation selectivity loss and, consequently, enhanced anion selectivity, especially in KOS1. Protamine addition to the lumen and bath similarly decreased <i>P</i>_Na/<i>P</i>_Cl values upon reduced luminal NaCl in the order of WTS1 > WTS3 > KOS3 > KOS1. Therefore, this study presents evidence of axial heterogeneity in paracellular transport across superficial PTs in mice.<b>NEW & NOTEWORTHY</b> Research on isolated perfused S2 segments of proximal tubules in mice, both expressing and lacking claudin-2, indicates that claudin-2 forms leaky monovalent cation-selective paracellular channels within the tight junctions of proximal tubules. This study characterized the paracellular transport properties in isolated and perfused superficial proximal tubule S1-S3 segments in both groups of mice. The findings demonstrate, for the first time, functional heterogeneity in the paracellular pathway along the axis of the superficial proximal tubules.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F1067-F1078"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549488","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}