Sirtuin and metabolic kidney disease

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. 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. Recently, there has been an explosion of studies on sirtuin in health and diseases. The founding member of the sirtuin gene family was originally found in yeast as silent information regulator 2, Sir2.1.Kim S. Benguria A. Lai C.Y. et al.Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae.Mol Biol Cell. 1999; 10: 3125-3136Crossref PubMed Scopus (182) Google Scholar In 1986, the Sir2 gene was isolated and identified as a gene associated with lifespan of cells from yeast.2.Ivy J.M. Klar A.J. Hicks J.B. Cloning and characterization of four SIR genes of Saccharomyces cerevisiae.Mol Cell Biol. 1986; 6: 688-702Crossref PubMed Scopus (211) Google Scholar In late 1990s, a study demonstrated that deletion of Sir2 shortens yeast life span and that Sir2 overexpression extends yeast life span.3.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. 1999; 13: 2570-2580Crossref PubMed Scopus (1761) Google Scholar Sir2 came to be known as a longevity-related factor.4.Bordone L. Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity.Nat Rev Mol Cell Biol. 2005; 6: 298-305Crossref PubMed Scopus (846) Google Scholar However, a possible mechanism was not elucidated until a study showing the true enzyme activity of Sir2 as a nicotine amide dinucleotide (NAD+)–dependent histone deacetylase.5.Imai S. Armstrong C.M. Kaeberlein M. et al.Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase.Nature. 2000; 403: 795-800Crossref PubMed Scopus (2781) Google Scholar Sir2 comprises the class II family of histone deacetylase enzymes. Unlike class I and class II, which requires only zinc as a cofactor, Sir2 depends on NAD+ for activation. In the presence of NAD+, Sir2 catalyzes the conversion of an acetylated substrate to a deacetylated substrate with O-acetyl-ADP-ribose and nicotinamide as side products.6.Guarente L. Franklin H. Epstein lecture: sirtuins, aging, and medicine.N Engl J Med. 2011; 364: 2235-2244Crossref PubMed Scopus (425) Google Scholar Sirtuins are mammalian homologs of Sir2, which are composed of seven isoforms Sirt1 to Sirt7. These seven isoforms share the same universal catalytic core region composed of 275 amino acids and show a diverse subcellular localization. Sirt1, Sirt6, and Sirt7 are mainly found in the nucleus, Sirt2 is in the cytoplasm, while Sirt3, Sirt4, and Sirt5 are localized in mitochondria.7.Mouchiroud L. Houtkooper R.H. Auwerx J. NAD+ metabolism: a therapeutic target for age-related metabolic disease.Crit Rev Biochem Mol Biol. 2013; 48: 397-408Crossref PubMed Scopus (149) Google Scholar Among the seven isoforms, Sirt1 is the most studied, is homologous to Sir2, and is induced by calorie restriction, which has been verified as a life-extending process in mammals (Figure 1). Since substrates of Sirt1 vary from transcription factors that are involved in energy metabolism, including glucose and lipid metabolism, Sirt1 may have an