Inhibition of Nicotinamide N-Methyltransferase (NNMT), Linked to Progression of Human CKD, Blocks Kidney Injury in a Mouse Model of Diabetic Kidney Disease

Le résumé fourni par la source

Background: Therapeutic strategies for chronic kidney disease (CKD) linked directly to the understanding of intra-kidney pathophysiology and progression are limited. A molecular signature linked to CKD progression was used to identify and develop a new class of treatment options. Methods: A transcriptome-driven analysis of kidney biopsies from CKD patients with longitudinal follow up (N=309) was used to identify genes associated with disease severity and progression, which was evaluated by GFR slope and composite endpoint of kidney failure and 40% GFR reduction. Expression of NNMT was determined using single cell analysis and in situ hybridization. A small molecule inhibitor was identified, and its effects on renal cells and kidney injury in uninephrectomized (UNx) diabetic db/db mice were investigated. Results: NNMT was identified as one of the strongest predictors of baseline GFR (r=-0.66, FDR<0.05) in a genome-wide profiling study of kidney biopsies in European Renal cDNA Biobank. NNMT expression was detected in both glomeruli and tubulointerstitium. Tubulointerstitial NNMT mRNA at the time of biopsy was significantly (p<0.0001) correlated with interstitial fibrosis (r=0.64) and tubular atrophy (r=0.58). Association of NNMT with kidney disease progression was demonstrated by 1) its significant correlation with GFR slope (<0.0001); 2) higher NNMT is associated with increased risk of progression to composite endpoint in two CKD cohorts, C-PROBE and NEPTUNE. Overexpression of NNMT in HEK cells decreased cellular NAD+ levels. A novel small molecule NNMT inhibitor, AZ'8413, restored NAD+ levels in NNMT-overexpressing cells and increased NAD+ in human proximal tubule cells. In db/db UNx mice, AZ'8413 decreased the progression of glomerular mesangial expansion and tubular injury. Kidney expression of Sirt1 increased, while ROS-producing enzymes and urinary markers of lipid peroxidation decreased. Conclusion: Our integrative study identifies NNMT as a promising target and validates NNMT inhibitors as novel therapeutics for mitigating CKD progression. Funding: Commercial Support - AstraZeneca

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.