| Popis: |
Ketogenic diet (KD) and β-Hydroxybutyrate (βOHB) has been widely reported as an effective therapy for metabolic diseases. β-hydroxybutyrate dehydrogenase 1 (Bdh1) is the rate-limiting enzyme of ketone metabolism. In this study, we investigated the Bdh1-mediated βOHB metabolic pathway in pathogenesis of diabetic kidney disease (DKD). Human renal tubule epithelial cells (HK-2 cells) induced by high glucose (HG) or palmitic acid (PA) were used to transfect with Bdh1 siRNA or plasmid-flag-Bdh1. Reactive oxygen species (ROS) levels, nuclear factor red 2-related factor 2 (Nrf2) protein expression, and βOHB-acetoacetate (AcAc)-succinate-fumarate metabolic flux were detected. Five-week-old C57 BKS db/db obese diabetic mice (db/db) and their littermate controls (+/+) were treated with KD, βOHB, and adeno-associated virus (AAV9)-Bdh1, respectively. Renal function was determined by urinary albumin/creatinine ratio (ACR), and histopathological, immunohistochemistry (IHC), TUNEL staining of kidney were also performed. The renal expression of Bdh1 was down-regulated in DKD mouse models, diabetic patients and HG or PA induced HK-2 cells. Bdh1 overexpression or βOHB treatment protected HK-2 cells from glucotoxicity and lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism activated Nrf2 through enhancement of metabolic flux composed of βOHB-acetoacetate-succinate-fumarate. Moreover, in vivo studies showed that AAV9-mediated Bdh1 renal expression successfully reversed the fibrosis, inflammation and apoptosis in kidneys from C57 BKS db/db mice. Notably, 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 pathogenesis of DKD and identified Bdh1 as a potential therapeutic target for DKD. |
