Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation

Abstract

Previous studies have shown that mitochondrial dysfunction plays an important role in high- glucose(HG)-induced podocyte injury and thus contributes to the progression of diabetic nephropathy(DN). The histone deacetylase Sirtuin6 (Sirt6) has been revealed to have an essential role in the regulation of mitochondrial function in skeletal muscle and cardiomyocytes. However, its specific role in mitochondrial homeostasis in podocytes is undetermined. Here, we aimeds to explore the physiological function of Sirt6 in podocyte mitochondria and apoptosis under HG conditions and explore the possible mechanism. Herein, we observed that Sirt6-WT-1 colocalization was suppressed in the glomeruli of patients with DN. In addition, diabetic mice exhibited reduced Sirt6 expression and AMP kinase (AMPK) dephosphorylation accompanied by mitochondrial morphological abnormalities. In vitro, podocytes exposed to HG presented with mitochondrial morphological alterations and podocyte apoptosis accompanied by Sirt6 and p-AMPK downregulation. In addition, HG promoted a decrease in mitochondrial number and an increase in mitochondrial superoxide production as well as a decreased mitochondrial membrane potential. ROS production was also increased in HG-treated podocytes. Conversely, all these mitochondrial defects induced by HG were significantly alleviated by Sirt6 plasmid transfection. Sirt6 overexpression simultaneously alleviated HG-induced podocyte apoptosis and oxidative stress, as well as increased AMPK phosphorylation. Increased levels of H3K9ac and H3K56ac induced by HG were attenuated in podocytes transfected with Sirt6 plasmids. Therefore, these results elucidated that Sirt6 protects mitochondria of podocytes and exerts anti-apoptotic effects via activating AMPK pathway. The present findings provide key insights into the pivotal role of mitochondria regulation by SIRT6 in its protective effects on podocytes.

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

“…65 Moreover, recent studies showed that SIRT6-mediated AMPK activation reduced mitochondrial dysfunction in either high-glucose-cultured podocytes or glycochenodeoxycholate-pretreated biliary epithelial cells. 66,67 Our results showed that SIRT6 and AMPK-PGC-1α-AKT signaling were further inhibited by diabetic MI/R injury. Long-term melatonin administration reduced the vulnerability of diabetic heart toward MI/R injury by preserving mitochondrial quality control and activating SIRT6 and AMPK-PGC-1α-AKT signaling.…”

Histone Deacetylases Take Center Stage on Regulation of Podocyte Function

“…2b). Recent studies have also found that Sirt6 protects mitochondria of podocytes and exerts antiapoptotic effects via activation of the AMP-activated protein kinase (AMPK) pathway [52]. Collectively, pharmacological targeting of Sirt6-mediated Notch signaling pathways at multiple levels may provide a novel approach for the treatment of proteinuric kidney disease.…”

Exogenous Hydrogen Sulfide Ameliorates Diabetic Myocardial Fibrosis by Inhibiting Cell Aging Through SIRT6/AMPK Autophagy

“…SIRT6 plays an important role in DNA repair and maintenance of genome stability, Participating in various physiological regulation mechanisms such as cell proliferation, differentiation and aging ( Gertler and Cohen, 2013 ), Recent studies have shown that SIRT6 can up-regulate AMP/ATP, then activate AMPK/Fox O3, Exerting antioxidant stress effect ( Wang et al., 2016 ), Fan et al. observed that overexpression of Sirt6 can increase AMPK phosphorylation level, The apoptosis of podocyte induced by HG was reduced ( Fan et al., 2019 ).At the same time, some studies have revealed that SIRT6 overexpression can inhibit senescence and apoptosis of nucleus pulposus cells by inducing autophagy ( Chen et al., 2018 ). Some studies pointed out that AMPK activity in aged and aging hearts is significantly reduced compared with young hearts, AMPK is an important regulatory kinase upstream of myocardial m TOR, which can inhibit the kinase activity of mTOR and activate autophagy to protect myocardium ( Ma et al., 2011 ).…”