Sirtuin and metabolic kidney disease

Abstract

Sirtuin is a nicotinamide adenine dinucleotide-dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti-fibrosis effects, anti-oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule-specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy.

Figure 1

Sirtuins and their functions. Sirtuin, a mammalian homolog of the Sir2 gene in yeasts, comprises seven isoforms. Sirt1, 6, and 7 are located predominantly in the nucleus, Sirt2 in cytoplasm, and Sirt3, 4, and 5 in mitochondria. These genes are activated or induced by calorie restriction or by acute cellular stresses mainly through increased levels of NAD⁺, thereby having a function in cellular survival. Changes contribute to longevity and organ protection. NAD, nicotine amide dinucleotide; Sirt, Sirtuin.

Figure 2

Nicotinic acid metabolism. NAD⁺, an essential factor in cellular respiration and metabolism, is produced through metabolism of nicotinic acid. NAD⁺ is synthesized via a de novo pathway from essential amino acid. NAD⁺ is also recycled through a salvage pathway where iNAMPT acts as a rate-limiting enzyme. In case NAD⁺ salvage was insufficient, Sirt1 activity decreased, further downregulating iNAMPT activity and salvage pathway. NAD, nicotine amide dinucleotide; Npt, nicotinic acid phosphoribosyltransferase; NaMN, nicotinic acid mononucleotide; Nmnat, nicotinamide mononucleotide adenylyltransferase; NMN, nicotinamide mononucleotide; iNAMPT, intracellular nicotinamide phosphoribosyltransferase; NMNAM, n-methylnicotinamide; Nnmt, nicotinamide n-methyltransferase.

Figure 3

Tubule–glomeruli communication hypothesis. Primary downregulation of Sirtuin (Sirt1) or iNAMPT reflects metabolic disruption of proximal tubular cells in the diabetic condition and initiates albuminuria. This downregulation decreases NMN excretion from proximal tubules, which is taken up by podocytes upstream and close to proximal tubules. Reduced uptake levels of NMN decrease Sirt1 expression in podocytes, which epigenetically upregulate claudin-1 expression through increased acetylation of histone H3K9 and through the hypermethylation of the claudin-1 gene CpG island. Ectopic overexpression of claudin-1 in podocytes disrupts the slit membrane structure via reduced expression of synaptopodin and podocin. This molecular change leads to changes in the podocyte structure and foot process effacement. Finally, the molecular events propagating proximal tubular cells to podocytes initiate albuminuria in diabetic nephropathy. NMN, nicotinamide mononucleotide; iNAMPT, intracellular nicotinamide phosphoribosyltransferase.

Figure 4

Scheme depicting the role of sirtuin in kidney disease. Sirt1 and Sirt3 have significant roles in the pathogenesis of various kidney diseases and in renal damage. These effects were targeted at various sites or cells of the kidney and at various downstream molecules that were subject to deacetylation or epigenetic gene regulation by sirtuin. AKI, acute kidney injury; MMP14, matrix metalloproteinase 14; NF-κB, nuclear factor-κB; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Sirt, Sirtuin.