Journal of The American Society of Nephrology最新文献

{"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":"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":"","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":"","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":"TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.","authors":"Giuseppina Grieco, Sandro Montefusco, Edoardo Nusco, Antonella Capuozzo, Francesca Cervellini, Elena Polishchuk, Martha Bishop, Antonio Miele, Luciano D'Apolito, Claudia La Vecchia, Miriam Aurilia, Michela Schiavo, Leopoldo Staiano, Marcella Cesana, Rebecca Oberman, Anna V Lynch, Patricia Musolino, Francesco Trepiccione, Yulia Grishchuk, Diego Luis Medina","doi":"10.1681/ASN.0000000567","DOIUrl":"https://doi.org/10.1681/ASN.0000000567","url":null,"abstract":"<p><strong>Background: </strong>Loss-of-function mutations in the lysosomal channel transient receptor potential cation channel (TRPML-1) cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood.</p><p><strong>Methods: </strong>A cross-sectional review of medical records from 21 patients with MLIV (ages 3–43 years) was conducted to assess kidney function impairment. In addition, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo kidney filtration measurements.</p><p><strong>Results: </strong>Of the 21 patients with MLIV, only adults were diagnosed with stage 2–3 CKD. Laboratory abnormalities included lower eGFR and higher levels BUN/creatine in blood and proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor–mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. In addition, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the proinflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, adeno-associated viral–mediated TRPML-1 gene delivery reversed key pathological phenotypes in MLIV mice, underscoring TRPML-1's critical role in kidney function.</p><p><strong>Conclusions: </strong>Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"36 4","pages":"587-601"},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764262","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":"Long-Term Results from an Open-Label Extension Study of Atacicept for the Treatment of IgA Nephropathy.","authors":"Jonathan Barratt, Sean J Barbour, Robert M Brenner, Kerry Cooper, Xuelian Wei, Necmi Eren, Jürgen Floege, Vivekanand Jha, Sung Gyun Kim, Bart Maes, Richard K S Phoon, Harmeet Singh, Vladimír Tesař, Richard Lafayette","doi":"10.1681/ASN.0000000541","DOIUrl":"10.1681/ASN.0000000541","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"679-687"},"PeriodicalIF":10.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502831","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}