The contralateral kidney presents with impaired mitochondrial functions and disrupted redox homeostasis after 14 days of unilateral ureteral obstruction in mice

Abstract

In unilateral ureteral obstruction (UUO), both oxidative stress and mitochondrial dysfunction are related to cell death. The aim of this study has been to characterize profiles of enzyme antioxidant activities and mitochondrial functioning of the contralateral (CL) compared to UUO and Sham (false-operated) kidneys of Balb/c mice. Kidneys were resected 14 days after obstruction for immunohistochemical and cortical mitochondrial functioning assays. Antioxidant enzymes activities were investigated in mitochondria and cytosol. Oxygen consumption (QO 2 ) and formation of O 2 reactive species (ROS) were assessed with pyruvate plus malate or succinate as the respiratory substrates. QO 2 decreased in CL and UUO in all states using substrates for complex II, whereas it was affected only in UUO when substrates for complex I were used. Progressive decrease in mitochondrial ROS formation–in the forward and reverse pathway at complex I–correlates well with the inhibition of QO 2 and, therefore, with decreased electron transfer at the level of complexes upstream of cytochrome c oxidase. CL and UUO transmembrane potential responses to ADP were impaired with succinate. Intense Ca 2+ -induced swelling was elicited in CL and UUO mitochondria. Important and selective differences exist in CL antioxidant enzymes with respect to either Sham or UUO kidneys: CL kidneys had increased mitochondrial glutathione peroxidase and cytosolic catalase activities, indicative of compensatory responses in the face of an early altered ROS homeostasis (as detected by 4-hydroxynonenal), and of a significant tendency to apoptosis. In CL and UUO, upregulation of nuclear (erythroid-derived 2)-like 2 transcription factor (Nrf2), as well as of cytoplasmic and nuclear Kelch-like ECH-associated protein 1 (Keap1) in opposition to decreased heme oxygenase-1 (HO-1), suggest impairment of the Nrf2/Keap1/HO-1 system. It is concluded that chronic obstruction impairs mitochondrial function in CL and UUO, preferentially affecting complex II.

Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

“…This mechanism is critical for regulating redox homeostasis in the kidney. In renal pathologies, Nrf2 is deactivated, leading to OS increase [60,61]. In the kidney, persulfides regulate blood pressure and sodium reabsorption.…”

DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

“…Previous studies have demonstrated that overexpression of DsbA-L has a renal-protective role against lipid-related kidney damage in DN 17 . In the current study, we initially induced DsbA-L in TGF-β1-treated BUMPT cells as well as in the kidneys of UUO mice and Ob patients, especially as the mitochondrion damage existed in the UUO model 27,28 ; we presumed that the expression of DsbA-L in kidney tubular injury was associated with the damage of mitochondrion damage (see Fig. 1 and Supplementary Fig.…”

Axl‐inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

“…In a previous study from our group, we found that tyrosine kinase receptor AXL is involved in the progression of renal fibrosis in a UUO murine model and that AXL inhibitor bemcentinib attenuates disease development 16 . Mitochondrial dysfunction and oxidative stress have been demonstrated to play a role in the pathogenesis of renal fibrosis in both, humans and animal models 24,25 . In this study, we investigated the effects of Axl‐inhibitor bemcentinib on mitochondrial dysfunction associated with renal fibrosis.…”

“…16 Mitochondrial dysfunction and oxidative stress have been demonstrated to play a role in the pathogenesis of renal fibrosis in both, humans and animal models. 24,25 In this study, we investigated the effects of Axl-inhibitor bemcentinib on mitochondrial dysfunction associated with renal fibrosis.…”