Obesity-induced arterial redox imbalance involving mitochondrial NOX4, endothelial dysfunction, and ER stress underlie kidney injury compensated by enhanced mitochondrial bioenergetics

Abstract

Mitochondrial reactive oxygen species (mtROS) are key pathogenic factors in the microvascular complications of metabolic disorders including nephropathy. However, the effects of obesity on kidney vascular mitochondria and endothelial function remain unclear. We assessed here the specific impact of obesity on endothelial function, mtROS-derived oxidative stress and mitochondrial bioenergetics of kidney preglomerular arteries in rat models of high fat diet (HFD)-induced obesity and endoplasmic reticulum (ER) stress. Arterial function was assessed in microvascular myographs, mitoSOX and Amplex Red fluorimetry were used to measure mtROS levels, and mitochondrial respiration was evaluated in renal preglomerular arteries by using an Agilent Seahorse XF Pro analyzer. Expression of mitochondria regulators and endoplasmic reticulum (ER) stress markers was analyzed by Western blot. We demonstrate here that HFD induces kidney injury and structural alterations including glomerulomegalia and fibrosis associated to redox imbalance with augmented mitochondrial superoxide, endothelial dysfunction, and endoplasmic reticulum (ER) stress in renal preglomerular arteries. Both HFD and ER stress lead to impaired biogenesis and down-regulation of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and NADPH oxidase 4 (NOX4), and lower levels of H2O2 that contribute to endothelial dysfunction. These changes are in turn associated with enhanced arterial mitochondrial respiration along with up-regulation of mitochondrial cytochrome c oxidase subunit 4 COX-IV likely related to hemodynamic changes in kidney preglomerular arteries leading to increased glomerular hyperfiltration rate (GFR) to supply function of injured glomeruli. The present findings therefore link adaptative changes in mitochondrial bioenergetics to obesity-induced impaired redox balance, endothelial dysfunction and ER stress in preglomerular arteries underlying kidney injury.