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CD38 inhibition by apigenin ameliorates mitochondrial oxidative stress through restoration of the intracellular NAD+/NADH ratio and Sirt3 activity in renal tubular cells in diabetic rats.


ABSTRACT: Mitochondrial oxidative stress is a significant contributor to the pathogenesis of diabetic kidney disease (DKD). We previously showed that mitochondrial oxidative stress in the kidneys of Zucker diabetic fatty rats is associated with a decreased intracellular NAD+/NADH ratio and NAD+-dependent deacetylase Sirt3 activity, and increased expression of the NAD+-degrading enzyme CD38. In this study, we used a CD38 inhibitor, apigenin, to investigate the role of CD38 in DKD. Apigenin significantly reduced renal injuries, including tubulointerstitial fibrosis, tubular cell damage, and pro-inflammatory gene expression in diabetic rats. In addition, apigenin down-regulated CD38 expression, and increased the intracellular NAD+/NADH ratio and Sirt3-mediated mitochondrial antioxidative enzyme activity in the kidneys of diabetic rats. In vitro, inhibition of CD38 activity by apigenin or CD38 knockdown increased the NAD+/NADH ratio and Sirt3 activity in renal proximal tubular HK-2 cells cultured under high-glucose conditions. Together, these results demonstrate that by inhibiting the Sirt3 activity and increasing mitochondrial oxidative stress in renal tubular cells, CD38 plays a crucial role in the pathogenesis of DKD.

SUBMITTER: Ogura Y 

PROVIDER: S-EPMC7343471 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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CD38 inhibition by apigenin ameliorates mitochondrial oxidative stress through restoration of the intracellular NAD<sup>+</sup>/NADH ratio and Sirt3 activity in renal tubular cells in diabetic rats.

Ogura Yoshio Y   Kitada Munehiro M   Xu Jing J   Monno Itaru I   Koya Daisuke D  

Aging 20200607 12


Mitochondrial oxidative stress is a significant contributor to the pathogenesis of diabetic kidney disease (DKD). We previously showed that mitochondrial oxidative stress in the kidneys of Zucker diabetic fatty rats is associated with a decreased intracellular NAD<sup>+</sup>/NADH ratio and NAD<sup>+</sup>-dependent deacetylase Sirt3 activity, and increased expression of the NAD<sup>+</sup>-degrading enzyme CD38. In this study, we used a CD38 inhibitor, apigenin, to investigate the role of CD38  ...[more]

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