Ability of NAD and Sirt1 to epigenetically suppress albuminuria

TL;DR

This study explores how NAD and Sirt1 can help prevent kidney damage in diabetes through epigenetic regulation.

Contribution

The study identifies new epigenetic pathways involving Sirt1 and Nampt in diabetic nephropathy progression.

Findings

NAD and its metabolites reduce albuminuria via Sirt1- or Nampt-dependent epigenetic regulation.

Proximal tubular Sirt1 deficiency leads to elevated Claudin-1 and albuminuria onset in early DN.

NMN, an NAD precursor, may regress DN by maintaining Sirt1 and repressing Claudin-1 in podocytes.

Abstract

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.

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