Qi Sun

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.

Podocytes, a type of highly specialized epithelial cells, require substantial levels of energy to maintain glomerular integrity and function, but little is known on the regulation of podocytes’ energetics. Lack of metabolic analysis during podocyte development led us to explore the distribution of mitochondrial oxidative phosphorylation and glycolysis, the two major pathways of cell metabolism, in cultured podocytes during in vitro differentiation. Unexpectedly, we observed a stronger glycolytic profile, accompanied by an increased mitochondrial complexity in differentiated podocytes, indicating that mature podocytes boost both glycolysis and mitochondrial metabolism to meet their augmented energy demands. In addition, we found a shift of predominant energy source from anaerobic glycolysis in immature podocyte to oxidative phosphorylation during the differentiation process. Furthermore, we identified a crucial metabolic regulator for podocyte development, pyruvate kinase M2. Pkm2-knockdown podocytes showed dramatic reduction of energy metabolism, resulting in defects of cell differentiation. Meanwhile, podocyte-specific Pkm2-knockout (KO) mice developed worse albuminuria and podocyte injury after adriamycin treatment. We identified mammalian target of rapamycin (mTOR) as a critical regulator of PKM2 during podocyte development. Pharmacological inhibition of mTOR potently abrogated PKM2 expression and disrupted cell differentiation, indicating the existence of metabolic checkpoint that need to be satisfied in order to allow podocyte differentiation.

Renal fibrosis is a final common pathway of chronic kidney disease. Sustained activation of fibroblasts is considered to play a key role in perpetuating renal fibrosis but the driving force in the perpetuation stage is only partially understood. To date, some investigations have specifically identified overexpression of microRNA 21 (miR-21) in the progression of kidney fibrosis. Nevertheless, the precise role of miR-21 in fibroblast activation remains largely unknown. In this study, we found that miR-21 was significantly upregulated in activated fibroblasts and that it maintained itself at constant high levels by employing an auto-regulatory loop between miR-21, PDCD4 and AP-1. Persistently upregulated miR-21 suppressed protein expression of Smad7 and, eventually, enhanced the TGF-β1/Smad pathway to promote fibroblast activation. More importantly, we found miR-21 sequestration with miR-21 antagomir or AP-1 inhibitors attenuated unilateral ureteral obstruction (UUO)-induced renal fibrosis. miR-21-knockout mice also suffered far less interstitial fibrosis in response to kidney injury. Altogether, these data suggest that miR-21 is a main driving force of fibroblast activation and keeps its high expression level by employing a double negative autoregulatory loop. Targeting this aberrantly activated feedback loop may provide new therapeutic strategy in treating fibrotic kidneys.