SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis

Abstract

Abstract. Diabetic nephropathy is a diabetic complication associated with capillary damage and increased mortality. Sirtuin 4 (SIRT4) plays an important role in mitochondrial function and the pathogenesis of metabolic diseases, including aging kidneys. The aim of the present study was to investigate the association between SIRT4 and diabetic nephropathy in a glucose-induced mouse podocyte model. A CCK-8 assay showed that glucose simulation significantly inhibited podocyte proliferation in a time-and concentration-dependent manner. Reverse transcription-quantitative polymerase chain reaction and western blot analysis showed that the mRNA and protein levels of SIRT4 were notably decreased in a concentration-dependent manner in glucose-simulated podocytes. However, SIRT4 overexpression increased proliferation and suppressed apoptosis, which was accompanied by increases in mitochondrial membrane potential and reduced production of reactive oxygen species (ROS). Notably, SIRT4 overexpression downregulated the expression of apoptosis-related proteins NOX1, Bax and phosphorylated p38 and upregulated the expression of Bcl-2 in glucose-simulated podocytes. In addition, SIRT4 overexpression significantly attenuated the inflammatory response, indicated by reductions in the levels of TNF-α, IL-1β and IL-6. These results demonstrate for the first time that the overexpression of SIRT4 prevents glucose-induced podocyte apoptosis and ROS production and suggest that podocyte apoptosis represents an early pathological mechanism leading to diabetic nephropathy.

SIRT4 enhances the sensitivity of ER‐positive breast cancer to tamoxifen by inhibiting the IL‐6/STAT3 signal pathway

“…STAT3 activation counteracted the effects of SIRT4, not only on the expression of tamoxifen resistance-related genes but also on cell proliferation. Similar to results obtained in glucose-stimulated podocytes, the release of IL-6 was reduced in ER-positive breast cancer cells when SIRT4 was overexpressed, 29 and after IL-6 treatment, SIRT4-induced inhibition of STAT3 was reversed. This indicates that SIRT4 enhances the sensitivity of ER-positive breast cancer to tamoxifen by inhibiting the IL-6/ STAT3 pathway.…”

Sirtuins and diabetes: optimizing the sweetness in the blood

“…Increased sirt4 expression downregulated the expression of apoptotic proteins like NOX1, Bax and phosphorylated p38 and upregulates Bcl-2 expression in glucose stimulated podocytes. These findings proves that Sirt4 overexpression prevents glucose induced podocyte apoptosis and ROS production in diabetic nephropathy [43].…”

Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer

“…This action, which seems nonenzymatic because the catalytically inactive mutant of Sirt4 H161Y is also able to block the Sirt3-MnSOD interaction, induces an increase of ROS levels and oxidative stress in the mitochondria of heart muscle cells and promotes cardiac hypertrophy (19). However, as mentioned, the overexpression of Sirt4 can prevent podocyte apoptosis induced by glucose with concomitantly increased mitochondrial membrane potential and reduced ROS production (32). These findings reveal that the effects of Sirt4 on mitochondrial ROS levels are context dependent.…”