Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology Vol. 32; no. 6; pp. 1355 - 1370
• Main Authors: Yasuda, Itaru, Hasegawa, Kazuhiro, Sakamaki, Yusuke, Muraoka, Hirokazu, Kawaguchi, Takahisa, Kusahana, Ei, Ono, Takashi, Kanda, Takeshi, Tokuyama, Hirobumi, Wakino, Shu, Itoh, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.06.2021
• Subjects: Albuminuria - etiology; Albuminuria - urine; Animals; Basic Research; Claudin-1 - metabolism; Cytokines - metabolism; Diabetic Nephropathies - complications; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; Dose-Response Relationship, Drug; Epigenesis, Genetic - drug effects; Glomerular Mesangium - pathology; Glycated Hemoglobin - metabolism; Histones - metabolism; Male; Mice; Mice, Knockout; NAD - metabolism; Nicotinamide Mononucleotide - administration & dosage; Nicotinamide Mononucleotide - therapeutic use; Nicotinamide Phosphoribosyltransferase - metabolism; Nicotinamide-Nucleotide Adenylyltransferase - metabolism; Podocytes - pathology; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Survival Rate; Time Factors; diabetic nephropathy
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2020081188

The activation of NAD -dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. Diabetic mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment. Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD salvage pathway, both of which indicate NMN legacy effects on DN.