NAD⁺ Anabolism Disturbance Causes Glomerular Mesangial Cell Injury in Diabetic Nephropathy

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-κB 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-κB 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.