Diabetic nephropathy (DN) is a research priority for scientists around the world because of its high prevalence and poor prognosis. Although several mechanisms have been shown to be involved in its pathogenesis and many useful drugs have been developed, the management of DN remains challenging. Increasing amounts of evidence show that silent information regulator 2 homolog 1 (sirtuin-1), a nicotinamide adenine dinucleotide (NAD+)–dependent protein deacetylase, plays a crucial role in the pathogenesis and development of DN. Clinical data show that gene polymorphisms of sirtuin-1 affect patient vulnerability to DN. In addition, upregulation of sirtuin-1 attenuates DN in various experimental models of diabetes and in renal cells, including podocytes, mesangial cells, and renal proximal tubular cells, incubated with high concentrations of glucose or advanced glycation end products. Mechanistically, sirtuin-1 has its renoprotective effects by modulating metabolic homeostasis and autophagy, resisting apoptosis and oxidative stress, and inhibiting inflammation through deacetylation of histones and the transcription factors p53, forkhead box group O, nuclear factor-κB, hypoxia-inducible factor-1α, and others. Furthermore, some microRNAs have been implicated in the progression of DN because they target sirtuin-1 mRNA. Several synthetic drugs and natural compounds have been identified that upregulate the expression and activity of sirtuin-1, which protects against DN. The present review will summarize advances in knowledge regarding the role of sirtuin-1 in the pathogenesis of DN. The available evidence implies that sirtuin-1 has great potential as a clinical target for the prevention and treatment of diabetes.

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Fenofibrate (FF) protects against diabetic nephropathy (DN) in type 1 diabetic (T1D) mice by upregulating the expression of fibroblast growth factor 21 (FGF21), leading to the activation of the Akt-mediated Nrf2 antioxidant pathways. Here, we examined which isoforms of Akt contribute to FF activation of FGF21-mediated renal protection by examining the phosphorylation and expression of three isoforms, Akt1, Akt2, and Akt3. T1D induced by a single intraperitoneal dose of streptozotocin (STZ) resulted in reduced phosphorylation of one isoform, Akt2, but FF treatment increased renal Akt2 phosphorylation in these and normal mice, suggesting a potential and specific role for renal Akt2 in FF protection against T1D. This was further confirmed using in vitro cultured HK-2 human kidney tubule cells exposed to high glucose (HG) with siRNA silencing of the Akt2 gene and STZ-induced diabetic Akt2-knockout mice with and without 3-month FF treatment. In normal HK-2 cells exposed to HG for 24 hours, FF completely prevented cell death, reduced total Akt expression and glycogen synthase kinase (GSK)-3β phosphorylation, increased nuclear accumulation of Fyn, and reduced nuclear Nrf2 levels. These positive effects of FF were partially abolished by silencing Akt2 expression. Similarly, FF abolished T1D-induced renal oxidative stress, inflammation, and renal dysfunction in wild-type mice, but was only partially effective in Akt2-KO mice. Furthermore, FF treatment stimulated phosphorylation of AMPKα, an important lipid metabolism mediator, which in parallel with Akt2 plays an important role in FF protection against HG-induced HK-2 cells oxidative stress and damage. These results suggest that FF protects against DN through FGF21 to activate both Akt2/GSK-3β/Fyn/Nrf2 antioxidants and the AMPK pathway. Therefore, FF could be repurposed for the prevention of DN in T1D patients.Key words: diabetic nephropathy; Akt2, fibroblast growth factor 21; nuclear factor erythroid 2-related factor 2; peroxisome proliferator-activated receptor α agonist.

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Ferroptosis is a type of regulated cell death characterized by iron-mediated lipid peroxidation, in contrast with apoptosis, autophagy, and necrosis. It can be triggered by many pathological processes, including cellular metabolism, tumors, neurodegenerative diseases, cardiovascular diseases, and ischemia–reperfusion injuries. In recent years, ferroptosis has been discovered to be associated with p53. P53 is a tumor suppressor protein with multiple and powerful functions in cell cycle arrest, senescence, cell death, repair of DNA damage, and mitophagy. Emerging evidence shows that ferroptosis plays a crucial role in tumor suppression by p53. P53 functions as a key bidirectional regulator of ferroptosis by adjusting metabolism of iron, lipids, glutathione peroxidase 4, reactive oxygen species, and amino acids via a canonical pathway. In addition, a noncanonical pathway of p53 that regulates ferroptosis has been discovered in recent years. The specific details require to be further clarified. These mechanisms provide new ideas for clinical applications, and translational studies of ferroptosis have been performed to treat various diseases.