title: SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis.
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.
authors.affiliation: Department of Endocrinology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Jian-Xia
authors.initials: JX
authors.lastname: Shi
authors.affiliation: Department of Endocrinology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Qi-Jin
authors.initials: QJ
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
keywords: apoptosis; diabetic nephropathy; glucose; podocytes; sirtuin 4