Sirtuin 1: A Target for Kidney Diseases

Abstract

Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent histone deacetylase that is necessary for caloric restriction-related lifespan extension. SIRT1, as an intracellular energy sensor, detects the concentration of intracellular NAD(+) and uses this information to adapt cellular energy output to cellular energy requirements. Previous studies on SIRT1 have confirmed its beneficial effects on cellular immunity to oxidative stress, reduction of fibrosis, suppression of inflammation, inhibition of apoptosis, regulation of metabolism, induction of autophagy and regulation of blood pressure. All of the above biological processes are involved in the pathogenesis of kidney diseases. Therefore, the activation of SIRT1 may become a therapeutic target to improve the clinical outcome of kidney diseases. In this review, we give an overview of SIRT1 and its molecular targets as well as SIRT1-modulated biological processes, with a particular focus on the role of SIRT1 in kidney diseases.

Figure 1

Renal tubule SIRT1 preserves podocyte function. Normally, SIRT1 in PT maintains glomerular NMN concentrations that lead to epigenetic silencing of claudin-1 promoter in podocytes. PT SIRT1 decreases in response to diabetes, followed by decreased glomerular NMN concentrations that in turn reduce SIRT1 expression in podocytes. Claudin-1 promoter is no longer silenced because of the downregulation of SIRT1. Consequently, high levels of claudin-1 in podocytes induce podocyte effacement and albuminuria.

Figure 2

Regulatory mechanisms of SIRT1 function and expression. , Stimulation; , inhibition; , tentative stimulation; , tentative inhibition.

Figure 3

The role of SIRT1 in the kidney. SIRT1 exerts renoprotective effects by preserving podocyte function, reducing fibrosis, inhibiting apoptosis, suppressing inflammation, inducing autophagy and EPO expression, regulating blood pressure and enhancing mitochondrial biogenesis through deaceylation of promoter-bound histones and several target proteins. →, Stimulation; ?, inhibition. Furthermore, SIRT1 protects the kidneys from renal diseases derived from diabetes and lipid metabolism disorders by deaceylation of IRS-2, SREBP, LXR and FXR. In addition, although study also showed that blocking SIRT1 attenuated renal interstitial fibrosis in obstructive nephropathy, the direct targets related to these effects remain unknown (see the detailed discussion in the text). Atgs, autophagy-related genes.