The inhibition of Nrf2 accelerates renal lipid deposition through suppressing the ACSL1 expression in obesity-related nephropathy

Abstract

Background: Obesity has become a worldwide epidemic, and the incidence of obesity is increasing year by year. Obesity-related nephropathy (ORN) is a common kidney complication of obesity. Long-chain acyl-CoA synthetases-1, (ACSL1), is a key enzyme in the oxidative metabolism of fatty acids in mitochondria and ACSL1 may play a direct role in renal lipid deposition and promote the progress of ORN. In this study, we focus on the renoprotective role of ACSL1 in ORN.Methods: Electron microscopy, immunohistochemical (IHC) staining, Western blot, and real-time PCR were used to detect the expression of ACSL1and Nrf2 in ORN patients, ob/ob mice and palmitic acid (PA)-treated HK-2 cells. Oil red staining and Elisa Kit were used to detect the intracellular FFA and TG contents in ob/ob mice and PA-treated HK-2 cells. Dihydroethidium (DHE) staining and the MDA/SOD measurement were used to detect the ROS production. In order to demonstrate the role of ACSL1 and the interaction between ACSL1 and Nrf2 in ORN, related siRNA and plasmid were transfected into HK-2 cells.Results: More ROS production and renal lipid deposition have been found in ORN patients, ob/ob mice and PA-treated HK-2 cells. Compared with control, all the expression of ACSL1and Nrf2 were down-regulated in ORN patients, ob/ob mice and PA-treated HK-2 cells. The Nrf2 could regulate the expression of ACSL1 and the ACSL1 played the direct role in renal lipid deposition.Conclusions: The Nrf2 is inhibited in ORN, resulting more ROS production and oxidative stress. Increased oxidative stress will suppress the expression of ACSL1, which could increase the intracellular FFA and TG contents, ultimately leading to renal lipid deposition in renal tubulars and accelerating the development of ORN.

Astragalosides IV Improves Palmitic Acid-induced Renal Tubular Epithelial Cells Injury Due to Inhibition of NLRP3 Inflammasome

“…The main saturated fatty acids, such as PA, has shown contributions to renal damage through increasing excessive ROS generation, apoptosis and endoplasmic reticulum (ER) stress [34,35]. In our previous studies, obvious renal lipid deposition and tubules damages were found in PA-induced HK-2 cells and T2DM rats [33,36]. In this study, we found that, with the prolongation of PA exposure, the cells viability was signi cantly decreased, and the apoptosis and lipids deposition were also signi cantly increased in HK-2 cells.…”

“…When the body's lipids are overloaded, the lipid balance is disrupted, leading to lipid metabolism system unable to proceed normally and cause lipotoxicity [31,32]. It has been reported that cellular lipotoxicity contributes to obesity-related nephropathy [33]. The main saturated fatty acids, such as PA, has shown contributions to renal damage through increasing excessive ROS generation, apoptosis and endoplasmic reticulum (ER) stress [34,35].…”

Molecular Characterization, Tissue Distribution Profile, and Nutritional Regulation of acsl Gene Family in Golden Pompano (Trachinotus ovatus)

“…Mammal studies showed that the ACSL1-6 are essential enzymes for the utilization of cellular LCFAs, which is the first enzyme to activate LCFAs, and determines their metabolic fate, including fatty acid β -oxidation, lipogenesis and signal lipids [ 2 , 20 ]. For example, ACSL1 and ACSL5 tend to be involved in fatty acids β -oxidation [ 21 , 22 ]. ACSL3 and ACSL4 mediate the lipid synthesis and lipid droplets biogenesis [ 23 , 24 ].…”

High-Fat Diet-Induced Renal Proximal Tubular Inflammatory Injury: Emerging Risk Factor of Chronic Kidney Disease

“…Lipids are the fundamental composition of cells. They present in the kidneys include triglycerides, phospholipids, cholesterol and its esters, and free fatty acids (FFAs; Hagve et al, 2001 ; Herman-Edelstein et al, 2014 ; Chen et al, 2019 ). In mammalian cells, FFAs are generated through the de novo synthetic pathway and released when triglycerides and phospholipids are hydrolyzed by cellular lipases ( Schaffer, 2003 ).…”