Journal of The American Society of Nephrology最新文献

{"title":"Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment.","authors":"Jennifer H Cox, Marc-Olivier Boily, Alexandre Caron, Tao Sheng, Joyce Wu, Jinyue Ding, Samuel Gaudreault, Oliver Chong, Jayakumar Surendradoss, Robert Gomez, Jeffrey Lester, Valerie Dumais, Xingsheng Li, Rajesh Gumpena, Matthew D Hall, Alex G Waterson, Gordon Stott, Andrew J Flint, William J Moore, W Todd Lowther, John Knight, M David Percival, Vincent Tong, Renata Oballa, David A Powell, Andrew J King","doi":"10.1681/ASN.0000000690","DOIUrl":"https://doi.org/10.1681/ASN.0000000690","url":null,"abstract":"<p><strong>Background: </strong>Primary hyperoxalurias 1-3 (PH1-3) are genetic diseases defined by elevated hepatic oxalate production and increased incidence of calcium oxalate kidney stones and potentially kidney failure. There are two approved agents available for PH1, and no approved therapies for PH2 or PH3. Lactate dehydrogenase A (LDHA) catalyzes the final step in hepatic oxalate synthesis and represents a potential therapeutic target for PH and other forms of hyperoxaluria associated with increased oxalate production.</p><p><strong>Methods: </strong>Potent and selective LDH inhibitors with liver-targeted tissue distribution were identified and characterized in enzymatic, cellular, and in vivo models.</p><p><strong>Results: </strong>We identified CHK-336, a novel oral small molecule that demonstrates potent and selective inhibition of the human LDH enzyme and its activity in hepatocyte assays across multiple species, including hepatocytes isolated from PH1 mice. CHK-336 demonstrated a favourable liver-distribution profile in mice, rats, and monkeys that was dependent on hepatic uptake by OATP transporters and target-mediated drug binding. In a rat pharmacodynamic model, CHK-336 inhibited conversion of 13C2-glycolate to 13C2-oxalate in a dose-dependent manner. In a PH1 mouse model, once-daily oral dosing of CHK-336 produced robust and dose-dependent reductions in urinary oxalate to the normal range. Seven days of treatment with CHK-336 also resulted in a significant reduction in urinary oxalate in a PH2 mouse model.</p><p><strong>Conclusions: </strong>In conclusion, CHK-336 is a potent, liver-targeted, small molecule LDH inhibitor that suppressed urinary oxalate production in a rat pharmacodynamic model and mouse models of PH1 and PH2.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Autoimmune Tubulopathies.","authors":"Pascal Houillier, Caroline Prot-Bertoye","doi":"10.1681/ASN.0000000723","DOIUrl":"https://doi.org/10.1681/ASN.0000000723","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezo1, F-actin Remodeling, and Podocyte Survival and Regeneration.","authors":"Maria Elena Melica, Giulia Antonelli, Roberto Semeraro, Gilda La Regina, Tommaso Dafichi, Camilla Fantini, Giulia Carangelo, Giuseppina Comito, Carolina Conte, Laura Maggi, Samuela Landini, Valentina Raglianti, Maria Lucia Angelotti, Alice Molli, Daniela Buonvicino, Letizia De Chiara, Elena Lazzeri, Benedetta Mazzinghi, Anna Julie Peired, Paola Romagnani, Laura Lasagni","doi":"10.1681/ASN.0000000697","DOIUrl":"https://doi.org/10.1681/ASN.0000000697","url":null,"abstract":"<p><strong>Background: </strong>Podocytes and podocyte progenitors are interdependent components of the kidney's glomerular structure, with podocytes forming the glomerular filtration barrier and progenitors being key players in podocyte regeneration during pathophysiological processes. Both cell types are subjected to constant mechanical forces, whose alterations can initiate podocytopathy and worsen glomerular injury. Despite this, the specific mechanosensors and mechanotransduction pathways involved in their response to mechanical cues remain only partially explored.</p><p><strong>Methods: </strong>We used transcriptomics, immunofluorescence, and silencing experiments on human primary podocyte progenitor cell cultures to demonstrate the expression and function of Piezo1 channels. We generated inducible podocyte- and podocyte progenitor-specific Piezo1 knockout mice to evaluate the effects of Piezo1 loss in the context of Adriamycin nephropathy and over 10 months of aging.</p><p><strong>Results: </strong>Silencing of Piezo1 in progenitors triggered F-actin remodelling, induced cell shape modification and nuclear envelope defects with accumulation of DNA damage that led to mitotic catastrophe in differentiated podocytes. Podocyte-specific knockout of Piezo1 induced higher susceptibility to podocyte injury in Adriamycin nephropathy and led to accumulation of DNA damage and mild albuminuria starting from adult age. Podocyte progenitor-specific knockout of Piezo1 in mouse resulted in severe albuminuria during Adriamycin nephropathy, leading to the generation of defective podocytes.</p><p><strong>Conclusions: </strong>These results demonstrated that Piezo1, thanks to its role in F-actin cytoskeleton maintenance, is essential for the survival of podocytes exposed to mechanical stress conditions and for their correct regeneration.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGLT2 Inhibitors Blunt Kidney Magnesium Wasting in Acute Cisplatin-Induced Hypomagnesemia with Effects on the TAL and DCT.","authors":"Erika F Jesus, Weverton M Luchi, Paulo C Castro, Flavia L Martins, Marcos V Caetano, Vanderlene L Kung, Antonio C Seguro, James A McCormick, Adriana C C Girardi","doi":"10.1681/ASN.0000000700","DOIUrl":"https://doi.org/10.1681/ASN.0000000700","url":null,"abstract":"<p><strong>Background: </strong>Cisplatin, a chemotherapeutic agent, induces kidney magnesium wasting and hypomagnesemia. Recent studies suggest that SGLT2 inhibitors elevate serum magnesium concentration in patients with or without diabetes. We hypothesized that the SGLT2 inhibitor empagliflozin attenuates acute cisplatin-induced hypomagnesemia by acting on the thick ascending limb (TAL) and distal convoluted tubule (DCT), key sites of magnesium reabsorption.</p><p><strong>Methods: </strong>Adult male Wistar rats received weekly treatments of cisplatin (2.5 mg/kg) or saline (vehicle) for five weeks. After three weeks, rats were randomized to receive empagliflozin (10 mg/kg/day) or water (vehicle) for the next fifteen days.</p><p><strong>Results: </strong>Cisplatin-treated rats developed significant hypomagnesemia with increased fractional excretion of magnesium (FEMg2+). Empagliflozin treatment reduced FEMg2+ and restored serum magnesium levels. In the TAL, cisplatin-treated rats had higher NKCC2 abundance but lower phosphorylated NKCC2 and claudin-16 levels than empagliflozin-treated cisplatin rats, whose protein levels were similar to controls. In contrast, claudin-19 abundance in the TAL was higher in cisplatin-treated rats than in controls and unaffected by empagliflozin treatment. In the DCT, cisplatin-treated rats displayed reduced abundance of the NaCl cotransporter (NCC), the magnesium channel TRPM6, and NCC phosphorylation, all of which were rescued by empagliflozin. Unexpectedly, cisplatin-treated rats exhibited higher mRNA expression and protein abundance of TRPM7 compared to empagliflozin-treated cisplatin rats, whose levels were similar to controls. Diuretic challenge tests with furosemide or hydrochlorothiazide confirmed reduced NKCC2 and NCC activity in cisplatin-treated rats. However, the natriuretic response to furosemide or hydrochlorothiazide did not differ between control and empagliflozin-treated cisplatin rats. Immunohistochemistry suggested that empagliflozin reversed cisplatin-induced DCT remodeling.</p><p><strong>Conclusions: </strong>Empagliflozin reduces kidney magnesium wasting and restores serum magnesium in cisplatin-treated rats, likely through reversing NKCC2 inhibition and claudin-16 downregulation in the TAL while normalizing NCC function and restoring TRPM6 expression in the DCT.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Authors' Reply: Balancing Feasibility and Efficacy: Reflections on Exercise Interventions for CKD Prevention in Older Adults.","authors":"Stein I Hallan, Ulrik Wisløff, Dorthe Stensvold, Knut A Langlo","doi":"10.1681/ASN.0000000685","DOIUrl":"https://doi.org/10.1681/ASN.0000000685","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal Ghrelin-Family GPR39 Receptor and Urinary Concentrating Ability.","authors":"Lingzhi Liu, Lena L Rosenbaek, Mackenzie Kui, Samuel L Svendsen, Annemette Overgaard Brethvad, Alexander Jakobsen, Laura V Sparsoe, Aimi Hamilton, Mads V Sørensen, Mathias Skov, Jacob R Therkildsen, Jesper Kingo Andresen, Anna Laitakari, Thomas M Frimurer, Boye Lagerbon Jensen, Jennifer Pluznick, Robert A Fenton, Birgitte Holst, Helle Praetorius","doi":"10.1681/ASN.0000000687","DOIUrl":"https://doi.org/10.1681/ASN.0000000687","url":null,"abstract":"<p><strong>Background: </strong>Low-calorie intake is associated with substantial changes in volume distribution and volume status in the body, resulting in reduced circulatory volume and a reduction in blood pressure. Activation of the orphan receptor GPR39 dampens food intake and causes weight loss in a GLP-1-dependent fashion. We speculated that appetite-regulating signaling might also be responsible for the circulatory volume contraction observed in response to anorectic states.</p><p><strong>Methods: </strong>To assess the effect of GPR39 fluid homeostasis, we combined in vivo, ex vivo, and in vitro studies to assess the effect of a selective GPR39 agonist (Cpd1324).</p><p><strong>Results: </strong>Oral gavage of Cpd1324 dose-dependently increased the water intake of wild-type (WT) C57BL/6J mice only and was completely absent in global GPR39 knockout (KO) mice. GPR39 is expressed in the distal convoluted tubule and collecting duct of the kidney, and WT mice exclusively showed Cpd1324-induced increase in urine production, increased K+ excretion, and reduced urine concentrating capacity both at baseline and after an 8-hour water restriction compared to vehicle controls. Correspondingly, Cpd1324 reduced AVP-induced cAMP production and directly counteracted the AVP-induced water permeability in perfused cortical collecting ducts. Moreover, specific GPR39 activation reduced the baseline and AVP-stimulated abundance of phosphorylated pS256-AQP2 and pT58-NCC and diminished the AVP-stimulated pS269-AQP2 abundance in renal tubular suspensions. These effects were seen exclusively in GPR39 wild-type mice and not in KO mice.</p><p><strong>Conclusions: </strong>These data suggest that Cpd1324 directly targets renal GPR39 to induce increased diuresis and consequently stimulate drinking behavior. We conclude that activation of GPR39 causes diuresis by opposing AVP-induced Na+ and Cl- reabsorption in the distal convoluted tubule and water reabsorption in the collecting duct.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Social Risk Factors with Kidney Function Recovery among Patients with Acute Kidney Injury Receiving Outpatient Dialysis.","authors":"Seda Babroudi, Hocine Tighiouart, Daniel E Weiner, Javier A Neyra, Ronald Sanders, Harold J Manley, Eduardo K Lacson, David A Drew","doi":"10.1681/ASN.0000000692","DOIUrl":"https://doi.org/10.1681/ASN.0000000692","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Balancing Feasibility and Efficacy: Reflections on Exercise Interventions for CKD Prevention in Older Adults.","authors":"Fan Zhang","doi":"10.1681/ASN.0000000684","DOIUrl":"https://doi.org/10.1681/ASN.0000000684","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Competing Risk Models Should Be Considered When Estimating Kidney Allograft Failure.","authors":"Jan H Lindeman, Hein Putter, Ian P J Alwayn, Esther Bastiaannet","doi":"10.1681/ASN.0000000629","DOIUrl":"10.1681/ASN.0000000629","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"747-748"},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double-Blind Placebo-Controlled Clinical Trial.","authors":"Hiddo J L Heerspink, Xiaoying Du, Yan Xu, Yanning Zhang, Bin Liu, Guangyu Bi, Chengyun Xu, Qun Luo, Henglan Wu, Jianxin Wan, Liou Cao, Rong Wang, Qiuling Fan, Hong Cheng, Lixia Xu, Jiyi Huang, Aimin Zhong, Qingfeng Peng, Yongjiang Hei, Yiwei Wang, Bo Zhou, Liqin Zhang, Jianghua Chen","doi":"10.1681/ASN.0000000538","DOIUrl":"10.1681/ASN.0000000538","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"657-667"},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}