Evidence of oxidative stress and mitochondrial respiratory chain dysfunction in an in vitro model of sepsis-induced kidney injury

Abstract

To investigate the role of oxidative stress and/or mitochondrial impairment in the occurrence of acute kidney injury (AKI) during sepsis, we developed a sepsis-induced in vitro model using proximal tubular epithelial cells exposed to a bacterial endotoxin (lipopolysaccharide, LPS). This investigation has provided key features on the relationship between oxidative stress and mitochondrial respiratory chain activity defects. LPS treatment resulted in an increase in the expression of inducible nitric oxide synthase (iNOS) and NADPH oxidase 4 (NOX-4), suggesting the cytosolic overexpression of nitric oxide and superoxide anion, the primary reactive nitrogen species (RNS) and reactive oxygen species (ROS). This oxidant state seemed to interrupt mitochondrial oxidative phosphorylation by reducing cytochrome c oxidase activity. As a consequence, disruptions in the electron transport and the proton pumping across the mitochondrial inner membrane occurred, leading to a decrease of the mitochondrial membrane potential, a release of apoptotic-inducing factors and a depletion of adenosine triphosphate. Interestingly, after being targeted by RNS and ROS, mitochondria became in turn producer of ROS, thus contributing to increase the mitochondrial dysfunction. The role of oxidants in mitochondrial dysfunction was further confirmed by the use of iNOS inhibitors or antioxidants that preserve cytochrome c oxidase activity and prevent mitochondrial membrane potential dissipation. These results suggest that sepsis-induced AKI should not only be regarded as failure of energy status but also as an integrated response, including transcriptional events, ROS signaling, mitochondrial activity and metabolic orientation such as apoptosis.

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

“…Mitochondrial oxidant generation in septic AKI plays an important role in renal tubular injury during sepsis, manifested as ischemic injury. 15,16,[35][36][37] Interestingly, mitochondria-targeted antioxidants could attenuate CLP-induced AKI, independent of systemic blood pressure. 17 Our findings showed that TLR9 deficiency helped to prevent renal mitochondrial injury and the subsequent decrease in renal function after CLP.…”

“…Recently, tubular oxidative stress and mitochondrial dysfunction were proposed as important pathologic changes occurring in septic AKI [15][16][17] ; however, little is known about effects of Tlr9KO on tubular dysfunctions after CLP. 11 Therefore, we evaluated the effects of Tlr9KO on tubular mitochondrial dysfunction after CLP.…”

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

“…[23][24][25] A large number of studies have shown that mitochondrial dysfunction plays an important role in the progression of renal disease including renal tubular injury, chronic kidney disease, and acute renal failure, which can lead to renal disease aggravation and progression. [26][27][28] More and more evidences suggested that the damage of mitochondrial morphological and function plays an important role in the development of DN. 29,30 Malik et al 31 found that mitochondrial DNA copy number of peripheral blood in patients with DN is significantly higher than the DM group without nephropathy, which prompted that mitochondrion plays a key role in DN, namely, mitochondrial fission is increasing under HG.…”

Mangiferin Attenuate Sepsis-Induced Acute Kidney Injury via Antioxidant and Anti-Inflammatory Effects

“…Until recently, several different patho-physiological mechanisms have been proposed for sepsis-induced AKI and a growing body of evidence now suggests that inflammatory reactions by systemic cytokine storm or local cytokine production [3], and tubular dysfunction induced by oxidative stress [5] are involved in the mechanisms of this complex and multi-factorial disease.…”