Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease

Abstract

Nicotinamide adenine dinucleotide (NAD+) supplies energy for deoxidation and anti-inflammatory reactions fostering the production of adenosine triphosphate (ATP). The kidney is an essential regulator of body fluids through the excretion of numerous metabolites. Chronic kidney disease (CKD) leads to the accumulation of uremic toxins, which induces chronic inflammation. In this study, the role of NAD+ in kidney disease was investigated through the supplementation of nicotinamide (Nam), a precursor of NAD+, to an adenine-induced CKD mouse model. Nam supplementation reduced kidney inflammation and fibrosis and, therefore, prevented the progression of kidney disease. Notably, Nam supplementation also attenuated the accumulation of glycolysis and Krebs cycle metabolites that occurs in renal failure. These effects were due to increased NAD+ supply, which accelerated NAD+-consuming metabolic pathways. Our study suggests that Nam administration may be a novel therapeutic approach for CKD prevention.

Impaired Nicotinamide Adenine Dinucleotide Biosynthesis in the Kidney of Chronic Kidney Disease

“…In unilateral urethral obstruction (UUO) mice model, NAM suppressed tubular atrophy, inflammation, and fibrosis (Zheng et al, 2019). In adenine-induced CKD mice model, NAM supplementation also reduced kidney inflammation and fibrosis and prevented the progression of kidney disease (Kumakura et al, 2021). Diabetic nephropathy (DN) is the leading cause of CKD worldwide (Alicic et al, 2017).…”

“…The current conclusions about the role of NAD + precursor supplementation in CKD are inconsistent. Kumakura et al (2021) demonstrated that NAM attenuated the progression of renal failure in a mouse model of adenine-induced CKD, while NR was found to not prevent CKD progression in UUO or chronic proteinuria (POD-ATTAC) mice models (Faivre et al, 2021). Both NAM and NR are first converted to NMN, and then, NAD + is synthesized under the catalysis of NMNATs.…”

NAD+, Senolytics, or Pyruvate for Healthy Aging?

“…This novel finding that was recognized by several Nobel laureates encouraged numerous studies, in vitro and in vivo, substantiating that NAD + and its precursors are apparently beneficial in preserving organ metabolism and function and postponing aging in animal models as well as patients. 8 - 11 …”

“…This novel finding that was recognized by several Nobel laureates encouraged numerous studies, in vitro and in vivo, substantiating that NAD + and its precursors are apparently beneficial in preserving organ metabolism and function and postponing aging in animal models as well as patients. [8][9][10][11] However, many clinical trials with NAD + or its precursors (NMN and NR) showed the indefinite clinical outcomes in past years. 12 Newly, the first clinical test with oral Niacin (NA) displayed remarkable salutary effects on patients with mitochondrial myopathy.…”

Metabolic Reprogramming and Renal Fibrosis

“…The proximal tubule cells account for 90% of the renal cortex and are the main adenosine triphosphate (ATP) consuming cells in the kidneys ( 30 ). Under normal physiological conditions, the renal tubular epithelial cells contain abundant mitochondria ( 31 ). These cells mainly rely on fatty acids (FAs) as fuel, and they generate energy by mitochondrial oxidative phosphorylation (OXPHOS) ( 32 ).…”