NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease

Komuraiah Myakala, Xiaoxin X. Wang, Nataliia V. Shults, Ewa Krawczyk, Bryce A. Jones, Xiaoping Yang, Avi Z. Rosenberg, Brandon Ginley, Pinaki Sarder, Leonid Brodsky, Yura Jang, Chan Hyun Na, Yue Qi, Xu Zhang, Udayan Guha, Ci Wu, Shivani Bansal, Junfeng Ma, Amrita Cheema, Chris AlbaneseMatthew D. Hirschey, Teruhiko Yoshida, Jeffrey B. Kopp, Julia Panov, Moshe Levi

Research output: Contribution to journalArticlepeer-review

Abstract

Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United -States. Despite 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 the progression of diabetic kidney disease.

Original languageEnglish (US)
Article number104975
JournalJournal of Biological Chemistry
Volume299
Issue number8
DOIs
StatePublished - Aug 2023

Keywords

  • NAD
  • cGAS-STING
  • diabetic kidney disease
  • inflammation, diabetes
  • mitochondria
  • mitochondrial DNA damage
  • sirtuin 3

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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