Limits...
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

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

License
getmorefigures.php?uid=PMC4593995&req=5

fig2: 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.

Mentions: As mentioned, Sirt1 catalyzes deacetylation with the aid of the coenzyme NAD+, the cellular level of which is important for its enzymatic activity. NAD+ is also important for oxidizing and reducing reactions as a coenzyme. NAD+ is synthesized through two biological pathways, these being de novo synthesis using an essential amino-acid tryptophan supplied by dietary intake, and a salvage pathway in which NAD+ is resynthesized from nicotinamide (NAM). The rate-limiting factor in the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes the synthesis of nicotinamide mononucleotide (NMN) from NAM and 5'-phosphoribosyl-1-pyrophosphate (Figure 2).13 Two NAMPT have been identified in mammals: intracellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT), found in the circulation. iNAMPT is known to be involved in energy metabolism.14 For instance, overexpression of iNAMPT in the liver suppresses induction of hepatic steatosis.15 It is also reported that systemic administration of iNAMPT-expression vector alleviates abnormal glucose tolerance.16 Calorie restriction increases the expression level of iNAMPT in muscles and mitochondria.17 These effects are possibly due to the activation of Sirt1, which is caused by activation of iNAMPT, followed by an increase in NAD+ supply. Activation of Sirt1 leads to activation of the salvage pathway through an increase in NAM and following activation of iNAMPT. At the same time, activation of Sirt1 leads to suppression of the clock genes, thereby reducing iNAMPT expression. This prevents excess activation of Sirt1 and iNAMPT and an excess in the positive feedback loop.18, 19 NAD, iNAMPT, and Sirt1 are currently recognized as important new factors in energy metabolism.


Sirtuin and metabolic kidney disease.

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

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

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

fig2: 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.
Mentions: As mentioned, Sirt1 catalyzes deacetylation with the aid of the coenzyme NAD+, the cellular level of which is important for its enzymatic activity. NAD+ is also important for oxidizing and reducing reactions as a coenzyme. NAD+ is synthesized through two biological pathways, these being de novo synthesis using an essential amino-acid tryptophan supplied by dietary intake, and a salvage pathway in which NAD+ is resynthesized from nicotinamide (NAM). The rate-limiting factor in the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes the synthesis of nicotinamide mononucleotide (NMN) from NAM and 5'-phosphoribosyl-1-pyrophosphate (Figure 2).13 Two NAMPT have been identified in mammals: intracellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT), found in the circulation. iNAMPT is known to be involved in energy metabolism.14 For instance, overexpression of iNAMPT in the liver suppresses induction of hepatic steatosis.15 It is also reported that systemic administration of iNAMPT-expression vector alleviates abnormal glucose tolerance.16 Calorie restriction increases the expression level of iNAMPT in muscles and mitochondria.17 These effects are possibly due to the activation of Sirt1, which is caused by activation of iNAMPT, followed by an increase in NAD+ supply. Activation of Sirt1 leads to activation of the salvage pathway through an increase in NAM and following activation of iNAMPT. At the same time, activation of Sirt1 leads to suppression of the clock genes, thereby reducing iNAMPT expression. This prevents excess activation of Sirt1 and iNAMPT and an excess in the positive feedback loop.18, 19 NAD, iNAMPT, and Sirt1 are currently recognized as important new factors in energy metabolism.

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