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Novel therapeutic strategies for chronic kidney disease (CKD) is limited by lack of understanding of its intra-kidney pathophysiology and progression. Molecular signature linked to CKD progression was used to develop a new class of treatment options.
A transcriptome-driven analysis of kidney biopsies from CKD patients with longitudinal follow up was used to identify genes associated with disease progression. Localization of NNMT was determined using single nuclei analysis and immunohistochemistry staining. A small molecule inhibitor was identified, and its effect on renal cells and kidney injury in uninephrectomized (UNx) diabetic db/db mice was investigated.
In search for kidney genes that can predict kidney function decline, our previous genome-wide profiling study of kidney biopsies from CKD patients from the European Renal cDNA Biobank identified tubulointerstitial NNMT mRNA as the strongest predictor of GFR within a six-gene panel. To understand the relationship between NNMT levels at the time of biopsy with CKD outcomes, we evaluated associations of NNMT mRNA levels with pathological and clinical parameters predictive of CKD outcomes. We observed significant correlations of NNMT mRNA levels with interstitial fibrosis (r=0.698) and tubular atrophy (r=0.688), with p<0.0001 for both. We further demonstrated that: 1) NNMT expression correlated with GFR slope (p<0.0001); and 2) higher NNMT levels predicted an increased risk of progression to kidney failure in patients (N=363) from two CKD cohorts, the Clinical Phenotyping Resource and Biobank Core and Nephrotic Syndrome Study Network (Fig. 1).
NNMT protein was primarily detected in the injured tubular epithelial cells , also in parietal epithelial cells. To investigate the underlying mechanism of NNMT association with adverse outcomes, we overexpressed NNMT in Human Embryonic Kidney (HEK) 293 cells and observed a substantial increase of 1-MNA, a downstream product of NNMT, and significantly decreased cellular NAD+ levels. A novel small molecule NNMT inhibitor, AZ8413, restored NAD+ levels in NNMT-overexpressing HEK cells to those observed in control cells. In human proximal tubule epithelial cells (RPTEC), inhibition of NNMT led to a significant increase in NAD+ levels. Genes dysregulated by overexpression of NNMT in HEK293 cells and reversed by NNMT knockdown in HK-2 human proximal tubule cells are enriched in canonical pathways related to fibrosis, immune response, axonal guidance, and production of reactive oxygen species. In a progressive DKD murine model, db/db UNx, AZ8413, administered via diet during week 18-22, decreased the progression of glomerular mesangial expansion and tubular injury (Fig. 2). Kidney expression of Sirt1 increased whereas ROS-producing enzymes and urinary markers of lipid peroxidation decreased, confirmed the in vitro bioinformatic analysis (Fig. 3).
Figure 1. Association of tubulointerstitial NNMT mRNA with patients’ kidney outcomes in patients with CKD. A) NNMT mRNA is significantly correlated with interstitial fibrosis (IF) and tubular atrophy (TA). B) Increased NNMT mRNA levels are significantly associated with an increased risk of progression to kidney failure (Likelihood ratio test, p<0.0001; N=321).
Figure 2. NNMT inhibitor AZ8413 decreased plasma 1-MNA, glomerular mesangial matrix expansion and tubular injury in db/db UNx mice. Mice were uninephrectomized at 8 weeks, dosed with AZ8413 via diet (3 or 90 mg/kg) between 18-22 weeks and then sacrificed. A) plasma 1-MNA B) glomerular extracellular matrix expansion C) tubular injury score (tubular injury, inflammation and fibrosis).
Figure 3. NNMT inhibition decreased lipid peroxidation, expression of ROS-generating enzymes and restored Sirt1 expression in db/db UNx mice. A) urine thiobarbituric acid reactive substances (TBARS, a measure of lipid peroxidation), Western blot analysis of B) Nox2 and C) Sirt1 protein in kidney homogenates.
* p<0.05 vs db/m lean, # p<0.05 vs db/db 18w, $ p<0.05 vs db/db 22w.
Our study reveals a significant association of NNMT with progression to kidney failure, and demonstrates its effects on key pathways of kidney pathogenesis. Inhibition of NNMT blocked both glomerular and tubulointerstitial injury in a DKD mouse model, highlighting its potential as a novel therapeutic target for mitigating CKD progression.
