Sirtuins and their relevance to the kidney

Abstract

Sirtuins (silent information regulator 2 [Sir2] proteins) belong to an ancient family of evolutionary conserved nicotinamide adenine dinucleotide (NAD)(+)-dependent enzymes with deacetylase and/or mono-ADP-ribosyltransferase activity. They regulate DNA repair and recombination, chromosomal stability, and gene transcription, and most importantly mediate the health-promoting effects of caloric restriction (CR), which includes the retardation of aging. At least seven Sir2 homologs, sirtuins (SIRT) 1 to 7 have been identified in mammals. Mammalian SIRT1, the most extensively studied family member, couples protein deacetylation with NAD(+) hydrolysis and links cellular energy and redox state to multiple signaling and survival pathways. Cell-type and context-specific activation of sirtuins increases resistance to metabolic, oxidative, and hypoxic stress in different tissues. In particular, SIRT1 plays a central role in mediating the beneficial effects of CR, and its activation associates with longevity and the attenuation of metabolic disorders. SIRT1 in the kidney is cytoprotective and participates in the regulation of BP and sodium balance. Here, we review sirtuin biology and discuss how CR-triggered sirtuin-dependent pathways affect renal physiology and the pathogenesis of kidney diseases and related disorders.

Figure 1

Sirtuin-mediated protein deacetylation requries NAD⁺. Overview of the sirtuin deacetylation reaction and the NAD⁺ salvage pathway. Sirtuins deacetylate their target proteins at specific lysine residues. This reaction is dependent on the availability of NAD⁺, which serves as a cosubstrate, thereby integrating cellular energy and redox state with multiple signaling and survival pathways. The reaction results in the formation of a deacetylated protein, NAM, and 2′-O-acetyl-ADP-ribose, and is inhibited by NAM. The salvage pathway (red arrows) is used to regenerate NAD⁺ from NAM. NAMPT, the rate-limiting enzyme in this pathway, converts NAM to NMN, followed by conversion of NMN to NAD⁺ by NMNAT.

Figure 2

Sirtuins protect kidney health. Shown is an overview of sirtuin-regulated processes with positive effect on kidney health. Nutritional cues and different forms of stress activate sirtuins in different tissues and cell types. This results in multiple local and systemic effects, which are likely to retard renal aging and result in renoprotection.