Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy
Itaru Yasuda, Kazuhiro Hasegawa, Yusuke Sakamaki, Hirokazu Muraoka, Takahisa Kawaguchi, Ei Kusahana, Takashi Ono, Takeshi Kanda, Hirobumi Tokuyama, Shu Wakino, Hiroshi Itoh
Abstract
Significance Statement Nicotinamide mononucleotide (NMN) is the precursor of NAD + that activates Sirtuin1 (Sirt1), an antiaging enzyme. Although some studies have administered NMN treatment in several disease models with favorable outcomes, NMN treatment in diabetic nephropathy has been scarcely examined. The authors showed a long-lasting renoprotective effect by transient pulse NMN administration in early DN in a murine model. Specifically, although NMN treatment did not change metabolic parameters, it attenuated decreased Sirt1, foot-process effacement of podocytes, and decreased albuminuria even long after pulse NMN treatment cessation. These findings indicate NMN is a potential preventive treatment in DN. Background The activation of NAD + -dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. Methods Diabetic db/db mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). Results At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in db/db 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 db/db 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. Conclusions: 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.