Sirtuins as novel pharmacological targets in podocyte injury and related glomerular diseases

Abstract

Podocyte injury is a major cause of proteinuria in kidney diseases, and persistent loss of podocytes leads to rapid irreversible progression of kidney disease. Sirtuins, a class of nicotinamide adenine dinucleotide-dependent deacetylases, can promote DNA repair, modify transcription factors, and regulate the cell cycle. Additionally, sirtuins play a critical role in renoprotection, particularly against podocyte injury. They also have pleiotropic protective effects on podocyte injury-related glomerular diseases, such as improving the immune inflammatory status and oxidative stress levels, maintaining mitochondrial homeostasis, enhancing autophagy, and regulating lipid metabolism. Sirtuins deficiency causes podocyte injury in different glomerular diseases. Studies using podocyte sirtuin-specific knockout and transgenic models corroborate this conclusion. Of note, sirtuin activators have protective effects in different podocyte injury-related glomerular diseases, including diabetic kidney disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, and lupus nephritis. These findings suggest that sirtuins are promising therapeutic targets for preventing podocyte injury. This review provides an overview of recent advances in the role of sirtuins in kidney diseases, especially their role in podocyte injury, and summarizes the possible rationale for sirtuins as targets for pharmacological intervention in podocyte injury-related glomerular diseases.

Keywords: Autophagy; Glomerular diseases; Immune and inflammation; Lipid metabolism; Mitochondrial homeostasis; Oxidative stress; Podocyte injury; Sirtuins.