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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

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.
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fig3: 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.

Mentions: Recently, the disease-initiating role of metabolic disruption in proximal tubular cells is reported in diabetic nephropathy, which is triggered by downregulation of Sirt1 (Figure 3).48


Sirtuin and metabolic kidney disease.

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

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

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

fig3: 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.
Mentions: Recently, the disease-initiating role of metabolic disruption in proximal tubular cells is reported in diabetic nephropathy, which is triggered by downregulation of Sirt1 (Figure 3).48

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