Fig. 1.

The molecular mechanisms of sirtuin-1 involvement in diabetic nephropathy. The changes in glucose metabolism in diabetes are associated with greater production of NADH and a reduction in the NAD+/NADH ratio, resulting in lower expression of sirtuin-1. Downregulation of sirtuin-1 causes greater acetylation of histones and several crucial transcription factors, such as STAT3, NF-κB, FoxO4, p53, HIF-1α, and Smad2/3, which increases their expression levels and transcriptional activation activities. Activation of STAT3 and upregulation of claudin-1 result in podocyte dysfunction. Acetylation of p66Shc facilitates its phosphorylation and translocation to the mitochondria, where it promotes hydrogen peroxide production. Activation of NF-κB signaling promotes the expression of its pro-inflammatory downstream effectors MCP-1, ICAM-1, VCAM-1, and NOX4. Acetylation of FoxO4 promotes expression of the pro-apoptotic gene BCL2 like 11, activating apoptosis. Acetylation of p53 stabilizes and activates it, resulting in target gene transcription, including that of p21 and Bax, inducing cell cycle arrest and apoptosis. Furthermore, the activation of Smad2/3 and HIF-1α induces fibrosis. HIF-1α and Flk-1 activate the VEGF pathway, causing abnormal angiogenesis. Lower expression of sirtuin-1 also leads to lower expression and/or inactivation of ACE2, FoxO1, FoxO3a, Nrf2, LKB1, TSC2, Atg8, Atg7, Atg5, and LC3, either directly (increase in acetylation) or indirectly. The inactivation of ACE2 removes its regulatory effect on Ang II and activates RAS. The inactivation of Nrf2 and the lower activity of FoxO1 and FoxO3a inhibit the expression of anti-oxidants such as Mn-SOD, CAT, GPs, HO-1, SOD, and NQO-1, which aggravates oxidative stress and mitochondrial dysfunction. The inactivation of LKB1 results in downregulation of the AMPK/PGC-1 pathway, which impairs autophagy and mitochondrial function, and promotes hypertrophy. As an inhibitor of the mTOR pathway, inactivation of TSC2 promotes activation of the mTOR pathway, which inhibits autophagy. Lower expression of Atg8, Atg7, Atg5, and LC3 impairs autophagy. Metabolic disturbance, oxidative stress, inflammation, impaired autophagy, hypoxia, abnormal angiogenesis, apoptosis, fibrogenesis, and activation of the RAS combine to cause the kidney lesions in diabetes