Kidney international最新文献_第2页

Restoration of branched chain amino acid catabolism improves kidney function in preclinical cardiovascular-kidney-metabolic syndrome models. 支链氨基酸分解代谢的恢复可改善临床前心血管-肾代谢综合征模型的肾功能。

IF 19.6 1区医学

Kidney international Pub Date : 2025-05-21 DOI: 10.1016/j.kint.2025.04.025

Eliza Bollinger,George Williams,Mary E Piper,Kimberly Steen,Kelly Tam Neale,Xian Chen,Mackenzie Marshall,Srinath Jagarlapudi,Yasaman Jami-Alahmadi,Pierre M Jean-Beltran,LouJin Song,Joshua Chiou,Frank Geoly,Sarah R Vargas,Ying Zhang,Elaine Kuang,Daniel Callahan,John C Stansfield,Max Russo,John Griffin,Zhongyuan Sun,Melissa R Miller,Craig L Hyde,Michelle F Clasquin,Katherine Hales,Natalie A Daurio,Justin D Crane,Dinesh Hirenallur-Shanthappa,John Groarke,Bei B Zhang,Rachel J Roth Flach

{"title":"Restoration of branched chain amino acid catabolism improves kidney function in preclinical cardiovascular-kidney-metabolic syndrome models.","authors":"Eliza Bollinger,George Williams,Mary E Piper,Kimberly Steen,Kelly Tam Neale,Xian Chen,Mackenzie Marshall,Srinath Jagarlapudi,Yasaman Jami-Alahmadi,Pierre M Jean-Beltran,LouJin Song,Joshua Chiou,Frank Geoly,Sarah R Vargas,Ying Zhang,Elaine Kuang,Daniel Callahan,John C Stansfield,Max Russo,John Griffin,Zhongyuan Sun,Melissa R Miller,Craig L Hyde,Michelle F Clasquin,Katherine Hales,Natalie A Daurio,Justin D Crane,Dinesh Hirenallur-Shanthappa,John Groarke,Bei B Zhang,Rachel J Roth Flach","doi":"10.1016/j.kint.2025.04.025","DOIUrl":"https://doi.org/10.1016/j.kint.2025.04.025","url":null,"abstract":"INTRODUCTIONPatients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs themselves are elevated in the myocardium of patients with HF, potentially due to a defect in BCAA catabolic breakdown. The rate limiting step of BCAA catabolism is the decarboxylation by the enzyme branched chain ketoacid dehydrogenase (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically.METHODSHere, using two pre-clinical CKM models, the hyperphagic ZSF1 obese rat and the uninephrectomized SDT fatty rat with high salt drinking water, we show that BCAA catabolic impairment is associated with and may be causal to CKM. Unbiased proteomic, transcriptomic and metabolomic profiling demonstrated impairment in BCAA catabolism within ZSF1 obese rat kidneys.RESULTSIn both CKM animal models, treatment with the BDK inhibitor BT2 improved urine protein content, kidney hypertrophy, and kidney pathology. Furthermore, coadministration of BT2 and the sodium-glucose cotransporter-2 inhibitor empagliflozin demonstrated additive effects to improve kidney parameters, kidney gene expression signatures, and kidney mitochondrial density and function.CONCLUSIONSOur study suggests that in addition to its previously reported effects on metabolism and cardiac function, BDK inhibition may also improve kidney health and therefore could represent a new therapeutic avenue for CKM.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"47 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130739","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}