Research Paper Volume 15, Issue 22 pp 13384—13410
BDH1-mediated βOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway
- 1 Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
- 2 Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, China
- 3 Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan 646000, China
- 4 Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
Received: August 1, 2023 Accepted: October 23, 2023 Published: November 27, 2023
https://doi.org/10.18632/aging.205248How to Cite
Copyright: © 2023 Wan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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 the BDH1-mediated βOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or βOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated βOHB metabolism activates NRF2 by enhancing the metabolic flux of βOHB-acetoacetate-succinate-fumarate. Moreover, in vivo studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS db/db mice. Either βOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.
Abbreviations
DKD: diabetic kidney disease; KD: ketogenic diet; TCA: tricarboxylic acid; βOHB: β-hydroxybutyrate; BDH1: β-hydroxybutyrate dehydrogenase 1; HG: high glucose; PA: palmitic acid; ROS: reactive oxygen species; NRF2: nuclear factor, erythroid-derived 2-like 2; AcAc: acetoacetate; AAV9: adeno-associated virus 9; DMF: dimethyl fumarate; H&E: hematoxylin-eosin; IHC: immunohistochemistry; IF: immunofluorescence; qRT-PCR: quantitative real-time PCR; WB: western blot; ACR: albumin to creatinine ratio.