NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease.

Autor:	Myakala K; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, USA., Wang XX; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, USA. Electronic address: Xiaoxin.Wang@georgetown.edu., Shults NV; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, USA., Krawczyk E; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, USA., Jones BA; Department of Pharmacology and Physiology, Georgetown University, Washington, District of Columbia, USA., Yang X; Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA., Rosenberg AZ; Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA., Ginley B; Departments of Pathology and Anatomical Sciences, SUNY, Buffalo, New York, USA., Sarder P; Department of Medicine-Quantitative Health, Department of Electrical and Computer Engineering, University of Florida, Gainesville, Florida, USA., Brodsky L; Tauber Bioinformatics Research Center, University of Haifa, Haifa, Israel., Jang Y; Department of Neurology, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA., Na CH; Department of Neurology, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA., Qi Y; Thoracic and GI Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Zhang X; Thoracic and GI Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Guha U; Thoracic and GI Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Wu C; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia, USA., Bansal S; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia, USA., Ma J; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia, USA., Cheema A; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia, USA., Albanese C; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia, USA., Hirschey MD; Division of Endocrinology, Metabolism, and Nutrition, and Pharmacology and Cancer Biology, Department of Medicine, Duke University, Durham, North Carolina, USA., Yoshida T; Kidney Disease Section, Kidney Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland, USA., Kopp JB; Kidney Disease Section, Kidney Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland, USA., Panov J; Tauber Bioinformatics Research Center, University of Haifa, Haifa, Israel., Levi M; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, USA. Electronic address: Moshe.Levi@georgetown.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Aug; Vol. 299 (8), pp. 104975. Date of Electronic Publication: 2023 Jul 08.
DOI:	10.1016/j.jbc.2023.104975
Abstrakt:	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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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