Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Jul;29(7):1799-1809.
doi: 10.1681/ASN.2017111218. Epub 2018 Apr 30.

Sirtuins in Renal Health and Disease

Marina Morigi  1 , Luca Perico  2 , Ariela Benigni  2
Affiliations
Review

Sirtuins in Renal Health and Disease

Marina Morigi et al. J Am Soc Nephrol. 2018 Jul.

Abstract

Sirtuins belong to an evolutionarily conserved family of NAD+-dependent deacetylases that share multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1-7) that are localized in different subcellular compartments. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regulating renal physiology. This review also details progress made in understanding the effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, highlighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. In this context, the current pharmacologic approaches to enhancing the activity of SIRT1 and SIRT3 will be discussed.

Keywords: Sirtuins; acute renal failure; chronic kidney disease; metabolism; mitochondria; sirtuin activators.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Sirtuins have broad enzymatic activities. (A) SIRT1, 2, 3, 5, 6, and 7 exhibit a lysine deacetylation activity of target proteins, in which the coenzyme NAD+ is consumed to generate nicotinamide (NAM) and 2′-O-acetyl-ADP-ribose (2′-OAADPr). (B) SIRT4 exclusively carries out ADP-ribosyl transferase activity, using NAD+ as the donor of the ADP-ribose group to the target proteins. ADP-ribosyl transferase activity is shared with SIRT6. (C) SIRT5 uses NAD+ as a cofactor to demalonylate and desuccinylate target proteins, generating NAM and 2′-O-malonyl-ADP-ribose (2′-OMADPr) and 2′-O-succinyl-ADP-ribose (2′-OSADPr), respectively.
Figure 2.
Figure 2.
Sirtuins contribute to maintain renal homeostasis and thei downregulation leads to chronic and acute kidney diseases. (A) Sirtuins are expressed throughout the different renal compartments. In the glomerulus (inset), SIRT1, SIRT3, and SIRT6 maintain the structural and functional integrity of podocytes. In close proximity to podocytes, glomerular endothelial cells express SIRT1, which controls systemic BP by regulating endothelial nitric oxide synthase (eNOS). SIRT1 is also ubiquitously expressed throughout all of the nephron segments and participates in sodium balance control and water reabsorption by regulating the α-subunit of the epithelial sodium channel (ENaC) in aquaporin 2-positive cells of the distal nephron. SIRT1 and SIRT3 are highly expressed in the proximal tubule, where they preserve mitochondrial functional integrity. In the collecting duct, SIRT7 controls acid–base and renal electrolyte handling through its ability to deacetylate the K+/Cl− cotransporter KCC4. (B) SIRT1, SIRT3, and SIRT6 exerts protective functions by modulating several renal targets (light blue). Downregulation of SIRT1, SIRT3, and SIRT6 favors the development of renal disorders (blue). BCL2, B cell lymphoma 2; DRP1, Dynamin related protein 1; FOXO4, Forkhead box protein O4; GSK3β, glycogen synthase kinase 3β; KIF5c, kinesin family member 5C; MMP-14, matrix metalloproteinase 14; OPA1, Optic atrophy 1; p53, tumor protein 53; PGC1-α, peroxisome proliferative activated receptor γ coactivator 1-α; Smad 3/4, Small mothers against decapentaplegic 3/4; STAT3, signal transducer and activator of transcription 3.
Figure 3.
Figure 3.
SIRT3 preserves the integrity of mitochondria and their intercellular shuttling between renal cells. Graphic representation depicting the functional activities of SIRT3 in the maintenance of proximal tubular epithelial cell homeostasis. In physiologic conditions (left), SIRT3 controls the global functional and structural integrity of mitochondria by sustaining ATP production and the activity of the antioxidant enzyme SOD2. This enables the constitutive trafficking of healthy organelles along the intact tubulin network via the anterograde motor protein Kif5c (left inset). After tubular cell injury (right), SIRT3 downregulation resulted in a remarkable ATP depletion, as well as impairment of SOD2 antioxidant activity. The downregulation of SIRT3 expression and activity also translates into unbalanced mitochondrial dynamics toward fission and fragmentation (right inset) by priming Drp1 recruitment on the mitochondrial outer membrane by binding to its receptor MFF, as well as reducing OPA1 expression. In association with fragmentation, loss of mitochondrial membrane permeability drives the disposal of dysfunctional organelles through PINK1-dependent mitophagy. The upregulation of SIRT3 expression and activity through pharmacologic manipulation with AICAR or ALCAR, as well as cell-based therapy with MSCs, counteracts mitochondrial dysfunction and restores the cell-cell exchange of healthy organelles between injured tubular cells. AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; ALCAR, acetyl-l-carnitine; Drp1, Dynamin related protein 1; Kif5c, kinesin family member 5C; ΔΨm, mitochondrial membrane potential; MMF, mitochondrial fission factor; OPA1, Optic atrophy 1; PINK1, PTEN-induced putative kinase 1.
See this image and copyright information in PMC

References

    1. Imai S, Armstrong CM, Kaeberlein M, Guarente L: Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800, 2000 - PubMed
    1. Kaeberlein M, McVey M, Guarente L: The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13: 2570–2580, 1999 - PMC - PubMed
    1. Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, Piper MD, et al. : Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477: 482–485, 2011 - PMC - PubMed
    1. Frankel S, Ziafazeli T, Rogina B: dSir2 and longevity in Drosophila. Exp Gerontol 46: 391–396, 2011 - PMC - PubMed
    1. Guarente L: Franklin H. Epstein lecture: Sirtuins, aging, and medicine. N Engl J Med 364: 2235–2244, 2011 - PubMed

Publication types