Sirtuins in kidney diseases: potential mechanism and therapeutic targets

Abstract

Sirtuins, which are NAD⁺-dependent class III histone deacetylases, are involved in various biological processes, including DNA damage repair, immune inflammation, oxidative stress, mitochondrial homeostasis, autophagy, and apoptosis. Sirtuins are essential regulators of cellular function and organismal health. Increasing evidence suggests that the development of age-related diseases, including kidney diseases, is associated with aberrant expression of sirtuins, and that regulation of sirtuins expression and activity can effectively improve kidney function and delay the progression of kidney disease. In this review, we summarise current studies highlighting the role of sirtuins in renal diseases. First, we discuss sirtuin family members and their main mechanisms of action. We then outline the possible roles of sirtuins in various cell types in kidney diseases. Finally, we summarise the compounds that activate or inhibit sirtuin activity and that consequently ameliorate renal diseases. In conclusion, targeted modulation of sirtuins is a potential therapeutic strategy for kidney diseases. Video Abstract.

Keywords: Endothelial cells; Kidney diseases; Macrophages; Podocyte; Renal tubular epithelial cells; Sirtuins.

Fig. 1

Location and distribution of sirtuins. NR, nicotinamide riboside; NMN, nicotinamide mononucleotide; NAD^+, nicotine adenine dinucleotide; NAM, nicotinamide; iNAMPT, intracellular nicotinamide phosphoribosyltransferase; Nmnat, nicotinamide mononucleotide adenylyltransferase. (Created with BioRender.com).

Fig. 2

Primary targets and cellular processes regulated by sirtuins in kidney diseases. HMGB1, high-mobility group box 1; HIF-1ɑ, hypoxia-inducible factor-1; STAT3, signal transducer and activator of transcription 3; YY1, Yin yang 1; eNOS, endothelial nitric oxide synthase; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; PINK1, PTEN-induced kinase 1; H3K56, histones3 lysine56; Nrf2, nuclear factor-erythroid 2-related factor 2; HO-1, heme oxygenase-1; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor kappa B; SOD, superoxide dismutase; PGC-1ɑ, peroxisome proliferator-activated receptor-gamma coactivator 1-alpha; NLRP3, NOD-like Receptor Pyrin Domain Containing 3; DRP1, dynamin-related protein 1; OPA1, optic atrophy 1; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase. (Created with BioRender.com)

Fig. 3

Molecular role of sirtuins in podocytes, endothelial cells, and mesangial cells. NF-κB, nuclear factor kappa B; SREBP1, sterol regulatory element-binding protein 1; H3K9, histones3 lysine9; Nrf2, nuclear factor-erythroid 2-related factor 2; eNOS, endothelial nitric oxide synthase; NLRP3, NOD-like Receptor Pyrin Domain Containing 3; SOD, superoxide dismutase; ROS, reactive oxygen species; HIF-1ɑ, hypoxia-inducible factor-1; FOXO, forkhead box O. (Created with BioRender.com)

Fig. 4

Molecular role of Sirtuins in proximal tubular epithelial cell, macrophages. SOD, superoxide dismutase; PINK1, PTEN-induced kinase 1; PGC-1ɑ, peroxisome proliferator-activated receptor-gamma coactivator 1-alpha; NF-κB, nuclear factor kappa B; Nrf2, nuclear factor-erythroid 2-related factor 2. (Created with BioRender.com)