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Sirtuin and metabolic kidney disease.

Wakino S, Hasegawa K, Itoh H - Kidney Int. (2015)

Bottom Line: Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig1: 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.

Mentions: 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 In 1986, the Sir2 gene was isolated and identified as a gene associated with lifespan of cells from yeast.2 In late 1990s, a study demonstrated that deletion of Sir2 shortens yeast life span and that Sir2 overexpression extends yeast life span.3 Sir2 came to be known as a longevity-related factor.4 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 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 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 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 important role in a number of biological processes like cell apoptosis, cell survival, longevity, and stress resistance. Human Sirt1 has been implicated to have a role in a number of age-related diseases like diabetes, neurodegenerative diseases, and kidney diseases. In particular, Sirt1 deacetylates uncoupling protein-1, peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor gamma coactivator α, and peroxisome proliferator-activated receptor γ and increases their activities.8 Hence, the functions of Sirt1 are intimately related to pathological conditions in diabetes and insulin resistance. Systemic and liver-specific Sirt1 knockout leads to insulin resistance in mice,9, 10 and adipose tissue–specific Sirt1 knockout increases obesity in high-fat diet-fed mice.11 In parallel with those observations, systemic Sirt1 transgenic mice show reduced insulin resistance,12 and adipose tissue–specific Sirt1 overexpression leads to reduced obesity in high-fat diet-fed mice.11 Thus, Sirt1 enables effective use of biogenic energy and increases insulin sensitivity.


Sirtuin and metabolic kidney disease.

Wakino S, Hasegawa K, Itoh H - Kidney Int. (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4593995&req=5

fig1: 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.
Mentions: 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 In 1986, the Sir2 gene was isolated and identified as a gene associated with lifespan of cells from yeast.2 In late 1990s, a study demonstrated that deletion of Sir2 shortens yeast life span and that Sir2 overexpression extends yeast life span.3 Sir2 came to be known as a longevity-related factor.4 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 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 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 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 important role in a number of biological processes like cell apoptosis, cell survival, longevity, and stress resistance. Human Sirt1 has been implicated to have a role in a number of age-related diseases like diabetes, neurodegenerative diseases, and kidney diseases. In particular, Sirt1 deacetylates uncoupling protein-1, peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor gamma coactivator α, and peroxisome proliferator-activated receptor γ and increases their activities.8 Hence, the functions of Sirt1 are intimately related to pathological conditions in diabetes and insulin resistance. Systemic and liver-specific Sirt1 knockout leads to insulin resistance in mice,9, 10 and adipose tissue–specific Sirt1 knockout increases obesity in high-fat diet-fed mice.11 In parallel with those observations, systemic Sirt1 transgenic mice show reduced insulin resistance,12 and adipose tissue–specific Sirt1 overexpression leads to reduced obesity in high-fat diet-fed mice.11 Thus, Sirt1 enables effective use of biogenic energy and increases insulin sensitivity.

Bottom Line: Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

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.

No MeSH data available.


Related in: MedlinePlus