American journal of physiology. Renal physiology最新文献

{"title":"Peak oxygen consumption is positively associated with estimates of oxygen extraction and microvascular blood volume in veterans with chronic kidney disease.","authors":"Jared M Gollie, Peter F Kokkinos, Samir S Patel, Alexander V Libin, Aaron B Holley, Nawar M Shara, Cooper G Hazel, David J Kim, Marc R Blackman","doi":"10.1152/ajprenal.00424.2025","DOIUrl":"10.1152/ajprenal.00424.2025","url":null,"abstract":"<p><p>Peak oxygen consumption (V̇o_2peak) is reduced in patients with chronic kidney disease (CKD). Although cardiovascular and skeletal muscle factors are implicated in the declines of V̇o_2peak, few studies have evaluated muscle oxygenation responses during exercise. We hypothesized that lower V̇o_2peak in CKD would be associated with attenuated responses in muscle oxygenation compared with those without CKD. Forty-six male Veterans [CKD stages 3 and 4, <i>n</i> = 23; referent controls (REF), <i>n</i> = 23] completed the study. Cardiopulmonary exercise testing was performed on a treadmill using the modified Bruce protocol. Peak change in dominant medial gastrocnemius deoxygenated hemoglobin/myoglobin {Δ[deoxy(Hb-Mb)]_peak}, total hemoglobin/myoglobin {Δ[total(Hb-Mb)]_peak}, tissue saturation index (ΔTSI), and ΔTSI reoxygenation half-time recovery (ΔTSI_reoxy1/2time) were assessed via near-infrared spectroscopy (NIRS). V̇o_2peak, exercise time, HR_peak, V̇o₂ at gas-exchange threshold (GET), and exercise time after GET were lower in the CKD group versus the REF group (<i>P</i> = 0.002, <i>P</i> < 0.001, <i>P</i> = 0.020, <i>P</i> = 0.044, and <i>P</i> = 0.005, respectively). For NIRS outcomes, Δ[total(Hb-Mb)]_peak was lower, and ΔTSI_reoxy1/2time prolonged, in the CKD group compared with the REF group (<i>P</i> = 0.032 and <i>P</i> = 0.031, respectively). V̇o_2peak was positively associated with HR_peak (CKD, <i>r</i> = 0.57, <i>P</i> = 0.005; REF, <i>r</i> = 0.63, <i>P</i> = 0.001) and Δ[total(Hb-Mb)]_peak (CKD, <i>r</i> = 0.63, <i>P</i> = 0.001; REF, <i>r</i> = 0.52, <i>P</i> = 0.012) in both groups. Conversely, V̇o_2peak was positively associated with Δ[deoxy(Hb-Mb)]_peak in the CKD group only (<i>r</i> = 0.64, <i>P</i> < 0.001). These findings suggest that skeletal muscle impairments, in addition to cardiovascular impairments, contribute to reduced V̇o_2peak in patients with CKD.<b>NEW & NOTEWORTHY</b> Peak oxygen consumption is associated with peak heart rate, oxygen extraction, and microvascular blood volume in patients with chronic kidney disease (CKD), highlighting the importance of cardiovascular and skeletal muscle health in this patient population. Future studies are necessary to determine which exercise approaches are most efficacious at enhancing cardiorespiratory fitness and whether, and to what extent, improvements in cardiorespiratory fitness result from changes in cardiovascular factors, skeletal muscle factors, or a combination of both.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F631-F640"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147655486","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":"Spoti-find: a novel, open-source void spot assay image analysis tool.","authors":"Cara C Hardy, Susan Sheehan, Seamus Mawe, Nick Sebasco, Will Ricke, Matt Mahoney, Ron Korstanje","doi":"10.1152/ajprenal.00441.2025","DOIUrl":"10.1152/ajprenal.00441.2025","url":null,"abstract":"<p><p>The void spot assay (VSA) is a widely used, noninvasive method for evaluating urinary behavior in rodents, but existing analysis tools are limited in scope, throughput, or accessibility. We developed Spoti-find, a stand-alone, open-source VSA image analysis application that introduces novel, biologically meaningful metrics including void circularity, distance to paper edge, and volume-based binning into primary, micro-, and nanovoids. Designed with usability in mind, Spoti-find features a graphical interface that enables manual or semiautomated spot identification, adjustable thresholds, and streamlined data export without the need for coding expertise. We validated Spoti-find across diverse datasets, showing strong interuser consistency, sensitivity to known phenotypes in aging and disease models, and accuracy in capturing novel parameters while demonstrating high agreement with existing tools. By capturing behavioral context and spatial morphology in voiding patterns, Spoti-find expands the interpretive power of VSA and provides a flexible, user-friendly platform for phenotyping urinary dysfunction in preclinical studies.<b>NEW & NOTEWORTHY</b> The VSA is a popular, noninvasive method for studying rodent urinary behavior, but current tools lack flexibility and require extensive manual quality control. We developed Spoti-find, an open-source application introducing novel parameters like void circularity, edge proximity, and volume-based binning. With a user-friendly interface requiring no coding, Spoti-find enables manual and semiautomated analysis with high consistency and transparency.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F513-F521"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147517535","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":"How does the kidney conserve Na⁺ in a salt-scarce environment?","authors":"Lawrence G Palmer, Alan M Weinstein, Gustavo Frindt","doi":"10.1152/ajprenal.00020.2026","DOIUrl":"10.1152/ajprenal.00020.2026","url":null,"abstract":"","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F601-F606"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647840","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":"Ovarian hormones moderate systolic hypertension in female <i>Eln</i> haploinsufficient mice.","authors":"Alethia J Dixon, Ipsita Mohanty, Gagandeep Kaur, James A McCormick, Patrick Osei-Owusu","doi":"10.1152/ajprenal.00485.2025","DOIUrl":"10.1152/ajprenal.00485.2025","url":null,"abstract":"<p><p>Hypertension is a hallmark of cardiovascular abnormalities associated with Williams syndrome (WS), a rare genetic disorder involving microdeletion of genes on human chromosome 7, including the elastin gene (<i>ELN</i>). Heterozygous deletion of <i>Eln</i> (<i>Eln^+/-</i>) in mice recapitulates hypertension and arteriopathy associated with WS. Previously, differences in blood pressure elevation and sensitivity to dietary sodium were found to be less profound in female <i>Eln^+/-</i> mice. Here, we determined whether ovarian hormones play a role in sex-related differences in blood pressure elevation resulting from <i>Eln</i> haploinsufficiency. Female <i>Eln^+/+</i> and <i>Eln^+/-</i> mice instrumented with radiotelemetry devices were subjected to sham surgery or ovariectomy (OVX). We found that OVX lowered diastolic but not systolic blood pressure (SBP) in <i>Eln^+/-</i> mice, resulting in increased pulse pressure. In <i>Eln^+/-</i> mice, diuresis induced by acute volume expansion was blunted, whereas antinatriuresis was exaggerated. Furthermore, amiloride lowered SBP and increased urinary Na⁺ excretion, suggesting that <i>Eln^+/-</i>-induced hypertension may be Na⁺-dependent. We conclude that increased Na⁺ and water retention by the kidney contribute to hypertension resulting from <i>Eln</i> haploinsufficiency. The underlying mechanism involves the alteration of ovarian hormone effects in the kidney and sustained signaling downstream of the V₂ receptor, leading to increased epithelial sodium channel (ENaC) activity and water reabsorption.<b>NEW & NOTEWORTHY</b> This study uncovers novel renal mechanisms by which <i>Eln</i> haploinsufficiency leads to systolic hypertension and the role of ovarian hormones in moderating blood pressure elevation. In female <i>Eln</i> haploinsufficient mice, ovarian hormone depletion elevates systolic blood pressure. <i>Eln</i> haploinsufficiency augments sodium and water reabsorption that is, in part, mediated by sustained activity of the vasopressin V₂ receptor and is associated with ENaC-dependent blood pressure elevation. These findings implicate abnormal sodium and water handling by the kidney as a contributing mechanism besides arteriopathy as the primary drivers of hypertension resulting from <i>Eln</i> haploinsufficiency.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F499-F512"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501049","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":"GPR183 contributes to renal macrophage infiltration and fibrosis in kidney injury.","authors":"Qian Zhang, Yan Wang, Yu Fan, Seung Seok Han, Han Xie, Eugene P Rhee, Donghai Wen","doi":"10.1152/ajprenal.00037.2026","DOIUrl":"10.1152/ajprenal.00037.2026","url":null,"abstract":"<p><p>Macrophages play a key role in kidney inflammation and fibrosis. The oxysterol receptor G protein-coupled receptor 183 (GPR183) is an important immunomodulatory receptor, but its role in kidney disease is undefined. In this study, we investigated the contribution of GPR183 to renal injury using adenine diet-induced chronic kidney disease and folic acid-induced nephropathy models. Both models exhibited marked upregulation of the cholesterol hydroxylases CH25H and CYP7B1, along with increased GPR183 expression in the kidney. Immunofluorescence analysis demonstrated that GPR183 colocalized with M1 macrophage markers within injured kidneys. Genetic deletion of GPR183 selectively reduced renal M1 macrophage accumulation and proinflammatory cytokine expression without affecting M2 macrophage infiltration, leading to improved renal function. GPR183 deficiency also significantly attenuated renal fibrosis, as evidenced by decreased collagen deposition and reduced expression of fibronectin and α-smooth muscle actin. In primary bone marrow-derived macrophages, GPR183 deletion suppressed lipopolysaccharide (LPS) and interferon γ (IFN-γ)-induced M1 polarization through inhibition of NF-κB signaling. Finally, analysis of publicly available human single-cell RNA sequencing data demonstrated substantial GPR183 expression in immune cells, including macrophages, in patients with chronic kidney disease. These findings identify GPR183 as a key regulator of macrophage phenotype in kidney injury and demonstrate that activation of the oxysterol-GPR183 axis promotes inflammatory and fibrotic renal remodeling. Targeting GPR183 may therefore represent a novel therapeutic strategy for the treatment of progressive kidney disease.<b>NEW & NOTEWORTHY</b> This study identifies GPR183 as a previously unrecognized regulator of macrophage polarization and renal fibrogenesis. We demonstrate that kidney injury activates an oxysterol-GPR183 signaling axis that promotes NF-κB-dependent M1 macrophage polarization. Genetic deletion of GPR183 selectively limits inflammatory macrophage accumulation, attenuates fibrosis, and preserves renal function, establishing GPR183 as a novel therapeutic target in progressive kidney disease.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F619-F630"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640500","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":"Characterization of α, β, and muscarinic receptor distribution in porcine ureters: a translational model for pharmacological ureteral dilation.","authors":"Victor Pham, Madison Rivero, Ahmet T Gundogdu, Caila Ruiz-May, Sophie Lawrence, Gokhan Gundogdu, Bruce Gao, Pengbo Jiang, Roshan Patel, Jaime Landman, Joshua Mauney, Ralph V Clayman, Yi Xi Wu","doi":"10.1152/ajprenal.00466.2025","DOIUrl":"10.1152/ajprenal.00466.2025","url":null,"abstract":"<p><p>Intraoperative ureteral dilation through smooth muscle relaxation is of interest for improving upper urinary tract access during retrograde intrarenal surgery. Porcine ureters are widely used translational models due to their anatomical similarities to humans; however, the distribution of receptors essential for pharmacological feasibility studies has not been fully characterized. This ex vivo study defines the regional expression of adrenergic and muscarinic receptors throughout the porcine ureter. Ureters from juvenile female Yorkshire swine (<i>n</i> = 4) were segmented into renal pelvis, proximal, middle, distal, and bladder cuff regions. Immunohistochemical (IHC) and histomorphometric analyses evaluated protein expression of α- and β-adrenergic receptor subtypes and muscarinic (M) subtypes. Quantitative-PCR assessed mRNA expression across ureteral regions; statistical analyses were performed using the Kruskal-Wallis test (IHC) and the Friedman test (qPCR), with Dunn's post hoc correction (<i>P</i> < 0.05). IHC demonstrated uniform distribution of α-, β-, M3, and M5 subtypes (<i>P</i> > 0.05). M1 expression was significantly higher in distal and bladder cuff regions versus proximal ureter (<i>P</i> = 0.0262), while M2 was elevated in the renal pelvis (<i>P</i> = 0.0134). All subtypes showed lower proximal immunoreactivity, and M4 was scantily detected. Most receptors are localized to the urothelium, except M3, which was also present in smooth muscle. qPCR confirmed expression of all receptor families except M4, with no regional differences in α-adrenergic or muscarinic transcripts. β-2 expression exceeded β-3 (<i>P</i> = 0.0439), and β-adrenergic transcripts were significantly higher than muscarinic (<i>P</i> = 0.0429). These results provide essential biological context for advancing translational research on the ureter.<b>NEW & NOTEWORTHY</b> This study provides the first comprehensive quantitative characterization of adrenergic and muscarinic receptor distribution throughout the porcine ureter using qPCR and immunohistochemistry. Novel findings include the first quantification of all β-adrenoceptor subtypes, revealing β-2 dominance (74% of β-receptors, 54% of total transcripts), and detection of M1 muscarinic receptor mRNA. α-1a/1d codominance mirrors human ureters. Predominant urothelial receptor localization suggests epithelial smooth muscle signaling. These data strengthen the understanding of porcine ureteral physiology for clinical and translational studies.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F522-F529"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147517522","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 urine metabolomic signature of distal diuretics and diuretic-induced hyponatremia in patients with chronic kidney disease.","authors":"Crissy F Rudolphi, Usha Musterd-Bhaggoe, George J G Ruijter, Ewout J Hoorn, Pedro H Imenez Silva","doi":"10.1152/ajprenal.00431.2025","DOIUrl":"10.1152/ajprenal.00431.2025","url":null,"abstract":"<p><p>Recent clinical trials have shown that distal nephron-acting diuretics are effective in managing fluid retention and salt-sensitive hypertension in people with chronic kidney disease (CKD). However, their use may be complicated by diuretic-induced hyponatremia. This study aimed to characterize the metabolomic effects of distal diuretics in people with CKD, including those who develop hyponatremia. Therefore, we analyzed plasma and 24-h urine samples from a previously completed randomized controlled trial including individuals with CKD (mean estimated glomerular filtration rate = 39 ± 13 mL/min/1.73 m²) treated with amiloride/hydrochlorothiazide (5 mg/50 mg daily) for 2 wk. The study included 26 participants in whom we analyzed a set of targeted metabolites. Global untargeted metabolomics was performed in a subcohort of 12 participants, including four patients who developed hyponatremia (plasma sodium <136 mmol/L) and eight diuretic-treated controls with stable sodium levels. Distal diuretic therapy decreased plasma glutamine levels and the excretion of several tricarboxylic acid cycle-related metabolites. Furthermore, distal diuretics significantly increased urinary ammonium excretion in the absence of hypokalemia or metabolic acidosis. Untargeted metabolomic analysis revealed 988 unique metabolites in the urine. Among those with hyponatremia, we observed a metabolomic signature of oxidative stress, likely due to altered glutamine and carnitine metabolism. These findings suggest that distal diuretics not only act locally in the distal convoluted tubule but also influence proximal tubular metabolism. In conclusion, our results highlight that distal diuretics induce significant metabolic changes in CKD, with urine metabolomics offering valuable insights into the physiological pathways and mechanisms underlying both therapeutic effects and adverse responses.<b>NEW & NOTEWORTHY</b> We assessed the urinary metabolomic fingerprint of treatment with amiloride and hydrochlorothiazide in individuals with CKD stages G3-G4. We identified enhanced ammoniagenesis in the absence of hypokalemia or metabolic acidosis. Patients who developed diuretic-induced hyponatremia exhibited a urinary metabolomic signature of oxidative stress. Our study highlights the interplay between \"electrolyte and fluid balance\" and \"metabolic adaptations\" in individuals with CKD who are treated with distal diuretics.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F607-F618"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147655534","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":"Stimulation of basolateral calcium-sensing receptor inhibits Kir4.1/Kir5.1 in the mouse distal convoluted tubule.","authors":"Junlin Wang, Jiawen Zhang, Shumin Kong, Ping Ma, Zhen Zhang, Lijun Wang, Wen-Hui Wang, Rui-Min Gu","doi":"10.1152/ajprenal.00339.2025","DOIUrl":"10.1152/ajprenal.00339.2025","url":null,"abstract":"<p><p>The calcium-sensing-receptor (CaSR) is expressed in the basolateral membrane of distal convoluted tubule (DCT) and CaSR expression inhibited Kir4.1 in cells expressing <i>Kcnj10</i>. The aim of the study is to explore whether CaSR inhibits Kir4.1/Kir5.1 in mouse DCT. We used patch-clamp technique to examine the effect of calcimimetics and increasing extracellular Ca²⁺ level on the basolateral Kir4.1/Kir5.1 in the DCT. Application of R-568, a CaSR agonist, decreased the 40-pS inwardly rectifying-K⁺ channel activity (Kir4.1/Kir5.1 heterotetramer), defined by NP_o (product of channel number and open probability), in the isolated DCT measured with cell-attached patches. This effect was completely abolished in the DCT treated with phospholipase-C (PLC) inhibitor or protein kinase C (PKC) inhibitor, suggesting that CaSR stimulation-induced inhibition of 40-pS K⁺ channel was due to activation of PLC-PKC pathway. Also, neomycin mimicked the effect of R-568 on the basolateral 40-pS K⁺ channel and decreased the 40-pS K⁺ channel activity. Again, this effect was completely abolished in the DCT treated with calphostin-C. Raising extracellular Ca²⁺ level to 5 mM reversibly inhibited the 40-pS K⁺ channel activity of the DCT and the washout was able to partially restore the channel activity. Moreover, the inhibition of PKC was able to completely abolish the inhibitory effect of 5 mM Ca²⁺ on the basolateral Kir4.1/Kir5.1 in the DCT. Finally, stimulation of CaSR with neomycin depolarized DCT cell membrane. We conclude that the activation of basolateral CaSR in the DCT inhibits Kir4.1/Kir5.1 and the effect of basolateral CaSR on the K⁺ channel is mediated by PLC-PKC pathway.<b>NEW & NOTEWORTHY</b> It is not known whether CaSR also inhibits Kir4.1/Kir5.1 in the native DCT. We have now used the patch-clamp experiments to directly demonstrate that the stimulation of CaSR in the basolateral membrane is able to inhibit Kir4.1/Kir5.1 in the mouse DCT and depolarize the DCT membrane potential. We speculate that the stimulation of CaSR-induced inhibition of Kir4.1/Kir5.1 may play a role in decreasing kidney Ca²⁺ excretion during hypocalcemia.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F555-F564"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13131289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522952","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 Cab39 adaptors results in KS-WNK1 independent accumulation of SPAK in biomolecular condensates.","authors":"Mohammed Zubaerul Ferdaus, Masa-Ki Inoue, Andrew S Terker, Paul A Welling, Eric Delpire","doi":"10.1152/ajprenal.00491.2025","DOIUrl":"10.1152/ajprenal.00491.2025","url":null,"abstract":"<p><p>The sodium-chloride cotransporter (NCC) in the distal convoluted tubule regulates renal sodium reabsorption, potassium homeostasis, and blood pressure. NCC phosphorylation is controlled by extracellular potassium via the with-no-lysine (WNK)-STE20/SPS1-related proline-alanine-rich kinase (SPAK) kinase cascade, proposed to initiate within biomolecular condensates termed WNK bodies. Kidney-specific with-no-lysine kinase (KS-WNK1) and calcium-binding protein 39 (Cab39) play different roles in WNK body formation and dissolution. Although KS-WNK1 is required for organizing WNK bodies, previous studies suggest that Cab39 promotes SPAK translocation from the WNK bodies to the apical membrane; Cab39 deletion traps phosphorylated SPAK in intracellular puncta and suppresses NCC phosphorylation. Whether these puncta represent bona fide WNK bodies or distinct condensates is unknown. To test whether SPAK puncta require KS-WNK1, we generated mice with distal convoluted tubule-specific deletion of both Cab39 isoforms and KS-WNK1 (triple knockout). NCC, phosphorylated SPAK, and WNK4 expression and localization were assessed by immunoblotting, immunofluorescence, and quantitative (PCR) under low- and high-potassium diets that activate or inhibit the WNK-SPAK-NCC pathway. Despite elevated WNK4, triple-knockout mice exhibited marked NCC hypo-phosphorylation. Phosphorylated SPAK accumulated in cytoplasmic puncta resembling WNK bodies even without KS-WNK1, indicating they are distinct from canonical WNK bodies. Under high-potassium conditions, when WNK4 and SPAK are dephosphorylated, these puncta were absent, suggesting dependence on upstream kinase activity. Thus, SPAK puncta form independently of KS-WNK1, previously considered necessary for WNK body formation, revealing distinct signaling condensates.<b>NEW & NOTEWORTHY</b> In this study, we identify novel biomolecular condensates (puncta) that appear in the absence of KS-WNK1, a component of WNK bodies. Mice knockout for both KS-WNK1 and Cab39 adaptor proteins exhibit large SPAK-containing puncta that also comprise WNK4 and L-WNK1. These puncta are p62-positive and ubiquitin-negative, indicating that they are sequestrating rather than degrading structures. Formation of these puncta requires active phosphorylation, as they are not observed in mice fed with a high K⁺ diet.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F541-F554"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576919","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":"Depletion of renal cortical collecting duct-secreted PCSK9 in early proteinuria prevents sustained nephrotic syndrome-related hypercholesterolemia.","authors":"Eduardo Molina-Jijon, Itzel Pamela Zavala-Guevara, Stéphanie Gambut, Tania Gomez-Sierra, Carmen Avila-Casado, Camille Macé, Lionel C Clement","doi":"10.1152/ajprenal.00350.2025","DOIUrl":"https://doi.org/10.1152/ajprenal.00350.2025","url":null,"abstract":"<p><p>The proprotein convertase subtilisin/kexin 9 (PCSK9) protein is well known for its role in the regulation of plasma cholesterol levels. We previously showed that the initiation of hypercholesterolemia in nephrotic syndrome is related to PCSK9 secreted by the cortical collecting duct (CCD), whereas the established phase is due to PCSK9 secreted by the liver. In this study, we investigated whether early neutralization of circulating CCD-secreted PCSK9 could prevent sustained hypercholesterolemia. We showed that PAN rats, a widely used animal model that mimics nephrotic syndrome phenotype of human minimal change disease (MCD), developed increased levels of PCSK9 of CCD origin prior to peak proteinuria. CCD-secreted PCSK9 followed an increase in the transcription factor sterol regulatory element-binding protein 2 (SREBP2) expression, while both SREBP2 and PCSK9 were unmodified and reduced, respectively, in the liver. Treatment of PAN rats with anti-PCSK9 antibodies administrated at or shortly after the onset of proteinuria prevented the development of significant and sustained hypercholesterolemia through the course of PAN. These data confirm that PCSK9 secreted from the kidney initiates the development of hypercholesterolemia in MCD and suggest that early depletion of PCSK9 during the initial stages of MCD prevents sustained hypercholesterolemia.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824582","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}