Insulin alleviates mitochondrial oxidative stress involving upregulation of superoxide dismutase 2 and uncoupling protein 2 in septic acute kidney injury

Abstract

The aim of the present study was to explore the effects and mechanisms of insulin on mitochondrial oxidative stress in septic acute kidney injury (AKI). Male Sprague Dawley rats were divided randomly into four groups: Control group, sham surgery group, cecal ligation and puncture (CLP) group, and CLP plus insulin group. Blood specimens and kidney tissues were obtained at 12 and 24 h after surgery as separate experiments. Analyses of histology and indicators of renal injury [blood urea nitrogen (BUN) and serum creatinine (CRE) and neutrophil gelatinase-associated lipocalin (NGAL)], mitochondrial function [adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP)], oxidative stress [inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) and nitric oxide (NO)], endogenous antioxidant systems [superoxide dismutase (SOD) and glutathione (GSH)] as well as the expression of uncoupling protein (UCP), PINK1 protein (a major mediator of mitophagy), PGC1α protein (a major regulator of mitochondrial biogenesis) were performed. Compared with CLP group, the CLP plus insulin group had milder histological damage, higher levels of ATP and MMP as well as lower levels of BUN, serum CRE and NGAL, intrarenal iNOS, mitochondrial ROS and total NO. Moreover, the CLP plus insulin group demonstrated increased expression of SOD2 and UCP2. In contrast, insulin administration suppressed mitophagy meanwhile did not upregulate total GSH and induce mitochondrial biogenesis following CLP. These findings indicated that the upregulation of SOD2 and UCP2 may be involved in insulin protecting against mitochondrial oxidative stress in septic AKI.

Time course of liver mitochondrial function and intrinsic changes in oxidative phosphorylation in a rat model of sepsis

“…Then, 12 h later, at the 36th hour from CLP, mitochondrial ROS generation increased again, inversely to the decrease in UCP2 mRNA concentration. Published evidence shows that UCP2 mRNA peaks from 6 to 24 h after CLP in heart and kidney [ 45 – 47 ] or endotoxic shock in liver cells [ 48 ] through proinflammatory cytokine activation. Even though we did not assess the uncoupling activity of UCP2 or do a protein assay, the variation of ROS generation observed was somehow inversely related to the expression of the UCP2 gene (Fig.…”

Chronic Insulin Infusion Down-Regulates Circulating and Urinary Nitric Oxide (NO) Levels Despite Molecular Changes in the Kidney Predicting Greater Endothelial NO Synthase Activity in Mice

“…We previously reported reduced protein levels of nNOS in the kidney in renal tubular Insr knockout mice (Insr fl/fl Ksp-Cre) [ 7 ]. Recently insulin therapy was shown to reduce renal mitochondrial iNOS expression, as well as, NO, in a rat model of septic shock [ 32 ]. The treatment, overall, reduced oxidative stress and attenuated renal damage and loss of function.…”

Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment

“…Several molecules have been studied in septic animal models to amend mitochondrial dysfunction, inflammation, and oxidative stress. 199 The notable exceptions are reltecimod (AB103; AtoxBio, Durham, NC), which is under active investigation to improve recovery from AKI (Phase 2 Study of Reltecimod Versus Placebo in Patients With Sepsis-associated Acute Kidney Injury, ), alkaline phosphatase, angiotensin II, and levocarnitine ( Table 3). Given that sepsis is the leading cause of AKI in the critically ill and given the dramatic effects from AKI on sepsis survival, it is our sincere hope that other companies will join the search for an S-AKI treatment.…”