RT Journal Article
SR Electronic
T1 NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.05.471273
DO 10.1101/2021.12.05.471273
A1 Komuraiah Myakala
A1 Xiaoxin X Wang
A1 Nataliia V. Shults
A1 Bryce A. Jones
A1 Xiaoping Yang
A1 Avi Z Rosenberg
A1 Brandon Ginley
A1 Pinaki Sarder
A1 Leonid Brodsky
A1 Yura Jang
A1 Chan Hyun Na
A1 Yue Qi
A1 Xu Zhang
A1 Udayan Guha
A1 Ci Wu
A1 Shivani Bansal
A1 Junfeng Ma
A1 Amrita Cheema
A1 Chris Albanese
A1 Matthew D Hirschey
A1 Teruhiko Yoshida
A1 Jeffrey B. Kopp
A1 Julia Panov
A1 Moshe Levi
YR 2022
UL http://biorxiv.org/content/early/2022/10/17/2021.12.05.471273.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.