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

J Am Soc Nephrol. 2021 Jun 1;32(6):1355-1370. doi: 10.1681/ASN.2020081188. Epub 2021 Apr 1.

Abstract

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.

Keywords: diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / etiology
  • Albuminuria / urine
  • Animals
  • Claudin-1 / metabolism
  • Cytokines / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Epigenesis, Genetic / drug effects
  • Glomerular Mesangium / pathology
  • Glycated Hemoglobin A / 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

Substances

  • Claudin-1
  • Cldn1 protein, mouse
  • Cytokines
  • Glycated Hemoglobin A
  • Histones
  • NAD
  • Nicotinamide Mononucleotide
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Dnmt1 protein, mouse
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse
  • Nicotinamide-Nucleotide Adenylyltransferase
  • Nmnat1 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1