SIRT5 induces glomerular sclerosis in diabetic nephropathy through p53

Abnormal proliferation of mesangial cells (MCs) and subsequent extracellular matrix (ECM) accumulation contribute to the glomerular sclerosis, which constitutes the primary pathological alteration in diabetic nephropathy (DN). The aim of this study was to identify the key factor (SIRT5) contributing to MCs proliferation in DN and explore the role and mechanism of SIRT5 in glomerular sclerosis. Proteomics technology and Ingenuity Pathway Analysis (IPA) database were employed to screen for SIRT5 as a key regulator of MC proliferation in DN mice. Co-immunoprecipitation (CO-IP) combined with mass spectrometry assay was utilized to identify the target protein (p53) of SIRT5. The effect of SIRT5 on MCs proliferation was evaluated in SIRT5 knocked-down or overexpressed MCs and 16-week-old mice. The expression of p53 target genes (p21 and 14-3-3σ) was assessed by real-time PCR and the succinylation of p53 was determined by CO-IP assay. The p53-siRNA was transfected into MCs to explore the mechanism by which SIRT5 modulates MCs proliferation. Results showed that elevated SIRT5 could induce the MCs proliferation, ECM accumulation and glomerular sclerosis. Notably, SIRT5 exerted its impact on p53 by regulating its transcriptional activity rather than its protein expression, which was due to the desuccinylation of p53 by SIRT5. Furthermore, once p53 in MCs was inhibited by p53-siRNA transfection, SIRT5 lost its ability to affect cell proliferation and ECM secretion. Collectively, these findings indicate that upregulated SIRT5 in MCs under high glucose condition reduces transcriptional activity of p53 through its desuccinylation effect, thereby promoting MCs proliferation and ECM secretion, and ultimately contributing to glomerular sclerosis in DN.