NAD+ Anabolism Disturbance Causes Glomerular Mesangial Cell Injury in Diabetic Nephropathy
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES(2022)
Abstract
The homeostasis of NAD(+) anabolism is indispensable for maintaining the NAD(+) pool. In mammals, the mainly synthetic pathway of NAD(+) is the salvage synthesis, a reaction catalyzed by nicotinamide mononucleotide adenylyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase (NMNATs) successively, converting nicotinamide (NAM) to nicotinamide mononucleotide (NMN) and NMN to NAD(+), respectively. However, the relationship between NAD(+) anabolism disturbance and diabetic nephropathy (DN) remains elusive. Here our study found that the disruption of NAD(+) anabolism homeostasis caused an elevation in both oxidative stress and fibronectin expression, along with a decrease in Sirt1 and an increase in both NF-kappa B P65 expression and acetylation, culminating in extracellular matrix deposition and globular fibrosis in DN. More importantly, through constitutively overexpressing NMNAT1 or NAMPT in human mesangial cells, we revealed NAD(+) levels altered inversely with NMN levels in the context of DN and, further, their changes affect Sirt1/NF-kappa B P65, thus playing a crucial role in the pathogenesis of DN. Accordingly, FK866, a NAMPT inhibitor, and quercetin, a Sirt1 agonist, have favorable effects on the maintenance of NAD(+) homeostasis and renal function in db/db mice. Collectively, our findings suggest that NMN accumulation may provide a causal link between NAD(+) anabolism disturbance and diabetic nephropathy (DN) as well as a promising therapeutic target for DN treatment.
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Key words
Sirt1,NAD(+),NMN,diabetic nephropathy,NMNAT1
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