Mito‐TEMPO Alleviates Renal Fibrosis by Reducing Inflammation, Mitochondrial Dysfunction, and Endoplasmic Reticulum Stress

Abstract

Background Renal fibrosis is a common pathological symptom of chronic kidney disease (CKD). Many studies support that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are implicated in the pathogenesis of CKD. In our study, we investigated the benefits and underlying mechanisms of Mito-TEMPO on renal fibrosis in 5/6 nephrectomy mice. Methods Mice were randomly divided into five groups as follows: control group, CKD group, CKD + Mito-TEMPO (1 mg·kg−1·day−1) group, CKD + Mito-TEMPO (3 mg·kg−1·day−1) group, and Mito-TEMPO group (3 mg·kg−1·day−1). Renal fibrosis was evaluated by PAS, Masson staining, immunohistochemistry, and real-time PCR. Oxidative stress markers such as SOD2 activity and MDA level in serum and isolated mitochondria from renal tissue were measured by assay kits. Mitochondrial superoxide production was evaluated by MitoSOX staining and Western blot. Mitochondrial dysfunction was assessed by electron microscopy and real-time PCR. ER stress-associated protein was measured by Western blot. Results Impaired renal function and renal fibrosis were significantly improved by Mito-TEMPO treatment. Furthermore, inflammation cytokines, profibrotic factors, oxidative stress markers, mitochondrial dysfunction, and ER stress were all increased in the CKD group. However, these effects were significantly ameliorated in the Mito-TEMPO treatment group. Conclusions Mito-TEMPO ameliorates renal fibrosis by alleviating mitochondrial dysfunction and endoplasmic reticulum stress possibly through the Sirt3-SOD2 pathway, which sheds new light on prevention of renal fibrosis in chronic kidney disease.

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

“…Here we observed that mito-TEMPO decelerates IPF-LF senescence in vitro, and in pre-clinical studies for asthma and kidney disease, mitoTEMPO exhibits antifibrotic activity. 1,45,46 In this study, the expression of PGC-1α was increased in IPF-LFs 48 These splice variants are regulated differently to PGC-1α1 and evoke distinct biological programs. 49 In this study, we provide evidence that an auto-feedback loop exists between dysfunctional mitochondrial and senescence in LFs, involving increases in mitochondrial superoxide and mTORC1 activation.…”

“…In this regard, mitoTEMPO and other mitochondrial‐selective antioxidants such as MitoQ show potential as therapies for lung fibrosis. Here we observed that mitoTEMPO decelerates IPF‐LF senescence in vitro, and in pre‐clinical studies for asthma and kidney disease, mitoTEMPO exhibits anti‐fibrotic activity …”

Mitochondria‐targeted antioxidant mito‐TEMPO alleviate oxidative stress induced by antimycin A in human mesenchymal stem cells

“…It has been reported that mito‐T is a potent mitochondria‐targeted antioxidant, which could act in ischemic tissues linked with hypoxia‐induced oxidative stress (Ding, Liu, Bi, & Zhang, 2017; Du et al, 2019; Du, Farhood, & Jaeschke, 2017; Li et al, 2018; Liu, Wang, Ding, & Wang, 2018; Nautiyal, Shaltout, Chappell, & Diz, 2019; Shetty, Kumar, & Bharati, 2019; Yang et al, 2018; Zhan et al, 2018). In the present study, mito‐T, a mitochondria‐targeted superoxide dismutase mimetic, dramatically reduced AMA‐induced mitochondrial oxidative stress, and thus effectively protected MSCs.…”

“…It has been reported that mito-T is a potent mitochondriatargeted antioxidant, which could act in ischemic tissues linked with hypoxia-induced oxidative stress (Ding, Liu, Bi, & Zhang, 2017;Du et al, 2019;Du, Farhood, & Jaeschke, 2017;Li et al, 2018;Liu, Wang, Ding, & Wang, 2018;Nautiyal, Shaltout, Chappell, & Diz, 2019;Shetty, Kumar, & Bharati, 2019;Yang et al, 2018;Zhan et al, 2018).…”

Acute spinal cord injury is associated with mitochondrial dysfunction in mouse urothelium

“…The bladders of mice with SCI were manually voided twice a day until the mice were used for experimental purposes. A separate group of animals had osmotic pumps (Alzet 1007D; Alzet, Cupertino, CA) implanted subcutaneously to deliver MitoTempo (1 mg/kg/day in 0.9% saline; Cayman Chemical, Ann Arbor, MI) at the time of the injury until sacrifice. Three days after injury , animals were killed (CO 2 followed by exsanguination) and bladder tissue was collected for the assays described below.…”