BDH1-mediated βOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway

• DOI: 10.18632/aging.205248
• Publication Date: 2023-11-27T17:50:52Z
• Authors: Sheng-Rong Wan; Fang-Yuan Teng; Wei Fan; Bu-Tuo Xu; Xin-Yue Li; Xiao-Zhen Tan; Man Guo; Chen-Lin Gao; Chun-Xiang Zhang; Zong-Zhe Jiang; Yong Xu
• Keywords: Mice; Hydroxybutyrate Dehydrogenase; 3-Hydroxybutyric Acid; NF-E2-Related Factor 2; Diabetes Mellitus; Animals; Humans; Diabetic Nephropathies; Kidney; Antioxidants; 3. Good health; Research Paper

A ketogenic diet (KD) and β-hydroxybutyrate (βOHB) have been widely reported as effective therapies for metabolic diseases.β-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism.In this study, we examined BDH1-mediated βOHB pathway pathogenesis of diabetic kidney disease (DKD).We found that BDH1 downregulated kidneys DKD mouse models, patients with diabetes, high glucose-or palmitic acid-induced human renal tubular epithelial (HK-2) cells.BDH1 overexpression or treatment protects HK-2 cells from glucotoxicity lipotoxicity by inhibiting reactive oxygen species overproduction.Mechanistically, metabolism activates NRF2 enhancing flux βOHB-acetoacetate-succinate-fumarate.Moreover, vivo studies showed adeno-associated virus 9-mediated expression successfully reverses fibrosis, inflammation, apoptosis C57 BKS db/db mice.Either supplementation KD feeding could elevate reverse progression DKD.Our results revealed a molecular mechanism identified potential therapeutic target DKD.