NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease

Abstract

Background: Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of all of the beneficial interventions implemented in patients with diabetes, there remains a need for additional therapeutic targets in diabetic kidney disease (DKD). Mitochondrial dysfunction and inflammation are increasingly recognized as important causes of the development and progression of DKD. However, the molecular connection between mitochondrial function, inflammation, and fibrosis remains to be elucidated. Methods: In the present studies we tested the hypothesis that enhancing NAD metabolism could increase mitochondrial sirtuin 3 (SIRT3) activity, improve mitochondrial function, decrease mitochondrial DNA damage, and prevent inflammation and progression of DKD. Results: We found that treatment of db-db mice with type 2 diabetes with nicotinamide riboside (NR) prevented albuminuria, increased urinary KIM1 excretion, and several parameters of DKD. These effects were associated with increased SIRT3 activity, improved mitochondrial function, and decreased inflammation at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. Conclusions: NR supplementation boosted the NAD metabolism to modulate mitochondrial function and inflammation and prevent progression of diabetic kidney disease.

Nicotinamide riboside activates renal metabolism and protects the kidney in a model of Alport syndrome

“…Although it has been known that NAD + supplementation protects from CKD (10)(11)(12)(13)(14), the cell types which were responsible for this benefit were not rigorously investigated. Models of AKI displayed the strongest and most consistent therapeutic benefit of NAD + supplementation, implying the proximal tubules as a likely location.…”

“…TD.190868, Envigo) for the remainder of the study. Administration of this dose of NR to mice via the diet has been reported previously (14). Photoplethysmography, echocardiography, and 24-hr urine collection were performed at 24-25 weeks old.…”

“…Recent data from our lab suggested that NAD + supplementation may modulate expression of metabolic genes in a model of diabetic CKD, although it was not the main focus of the study (14). In that study, we demonstrated that NR treatment restored mitochondrial function via sirtuin 3 activation, thereby preventing mitochondrial damage and subsequent leak of mitochondrial DNA into the cytosol.…”

Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway

“…[16] The recognition of aberrant DNA, particularly ectopic mtDNA, by the cGAS-STING signaling pathway plays a vital role in the innate immune response to kidney damage. [17–21]…”

NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

“…Overall, NA, NAM and NMN appear to exert a preventive role against the progression of CKD pathogenesis in preclinical models by attenuating histological and functional damage to the kidney, whereas NR does not consistently demonstrate beneficial effects in the studies cited above, despite increasing renal NAD + levels. Additional use of NR is under investigation in metabolic disease models (db/db diabetic mice) which may point at potential benefits in early-stage CKD, although the evidence is still under evaluation [178]. While this wealth of preclinical studies provides overall support to the clinical relevance of targeting NAD + metabolism in CKD, it also raises additional questions.…”