Abstract
Diabetic kidney disease (DKD) is currently one of the leading causes of end-stage renal disease (ESRD). Mitochondrial dysfunction in podocyte is involve in DKD development. However, whether early mitochondrial stabilization delays or reverses DKD progression has not been elucidated. SS31 is a novel tetrapeptide compound that targets the inner mitochondrial membrane and protects mitochondria by reducing ROS and inhibiting cardiolipin oxidation. Our study discovered that SS31 might have a long-term podocyte protection in DKD. In this study, we examined the glomerular pathological damage and proteinuria at different stages of diabetes. Results revealed that podocyte mitochondrial injury appeared at the early stage of DKD. Early treatment with SS31 could protect podocyte and alleviate the development of DKD via inhibiting OMA1-mediated hydrolysis of OPA1. Those data indicate that SS31 might be a promising agent in delaying the development of DKD and OMA1-mediated hydrolysis of OPA1 in mitochondria, and SS31 is a novel therapeutic target for the treatment of DKD.
Highlights
Diabetic kidney disease (DKD) is currently one of the leading causes of end-stage renal disease (ESRD) and is the strongest single predictor of mortality in diabetic patients (Reidy et al, 2014)
Electron microscopic photographs showed a marked basement membrane thickening and foot process widening at week 6 in mice from the STZ group and the slit diaphragm structures almost disappeared at week 20 (Supplementary Figure S1G–I). These results revealed that podocyte injury gradually worsened during the DKD progression
We reported that OMA1 activation-mediated hydrolysis of OPA1 participates in high glucose (HG)-induced podocyte
Summary
Diabetic kidney disease (DKD) is currently one of the leading causes of end-stage renal disease (ESRD) and is the strongest single predictor of mortality in diabetic patients (Reidy et al, 2014). It has been reported that mitochondrial abnormalities are involved in a variety of podocyte injury models (Guan et al, 2015; Szeto et al, 2016; Qi et al, 2017; Fujii et al, 2020), mitochondria-targeted drugs significantly alleviate podocyte injury, indicating that mitochondrial homeostasis plays an important role in podocytes (Szeto, 2017). Enough evidences show that abnormal mitochondrial dynamics is SS31 Ameliorates Podocyte Injury widely involved in podocyte injury (Wang et al, 2012; Yuan et al, 2018; Ma et al, 2019; Chen et al, 2020), and might be an important target for the treatment of podocyte diseases (Ayanga et al, 2016; Qin et al, 2019). We demonstrate that SS31 restores OPA1 expression by inhibiting OMA1 activation, and preserves mitochondrial function in podocyte during the progression of DKD
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