NAD metabolism modulates mitochondrial function and inflammation and prevents progression of diabetic kidney disease

Myakala, K.; Wang, X.; Jones, B. A.; Hirschey, M. D.; Yang, X.; Rosenberg, A. Z.; Ginley, B.; Sarder, P.; Brodsky, L.; Jang, Y.; Na, C. H.; Chi, Y.; Zhang, X.; Guha, U.; Lewien, P.; Wu, C.; Bansal, S.; Ma, J.; Cheema, A.; Panov, J.; Levi, M.

doi:10.1101/2021.12.05.471273

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bioRxiv · 10.1101/2021.12.05.471273

NAD metabolism modulates mitochondrial function and inflammation and prevents progression of diabetic kidney disease

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Abstract

Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of the beneficial interventions available for patients with diabetes, there remains a need for additional therapeutic targets and therapies in diabetic kidney disease (DKD). Inflammation and oxidative stress are increasingly recognized as important causes of renal diseases. Inflammation is closely associated with mitochondrial damage. The molecular connection between inflammation and mitochondrial metabolism remains to be elucidated. Recently, nicotinamide adenine nucleotide (NAD+) metabolism has been found to regulate immune function and inflammation. In the present studies we tested the hypothesis that enhancing NAD metabolism could prevent inflammation in and progression of DKD. We found that treatment of db/db mice with type 2 diabetes with nicotinamide riboside (NR) prevented several manifestations of kidney dysfunction (i.e., albuminuria, increased urinary kidney injury marker-1 (KIM1) excretion and pathologic changes). These effects were associated with decreased inflammation, at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. An antagonist of the serum stimulator of interferon genes (STING) and whole-body STING deletion in diabetic mice showed similar renoprotection. Further analysis found that NR increased SIRT3 activity and improved mitochondrial function, which led to decreased mitochondrial DNA damage, a trigger for mitochondrial DNA leakage which activates the cGAS-STING pathway. Overall, these data show that NR supplementation boosted NAD metabolism to augment mitochondrial function, reducing inflammation and thereby preventing progression of diabetic kidney disease.

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Myakala, K., Wang, X., Jones, B. A., Hirschey, M. D., Yang, X., Rosenberg, A. Z., Ginley, B., Sarder, P., Brodsky, L., Jang, Y., Na, C. H., Chi, Y., Zhang, X., Guha, U., Lewien, P., Wu, C., Bansal, S., Ma, J., Cheema, A., Panov, J., Levi, M.. 2021-12-07. NAD metabolism modulates mitochondrial function and inflammation and prevents progression of diabetic kidney disease. https://doi.org/10.1101/2021.12.05.471273

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