CXA-10, a Nitrated Fatty Acid, is Renoprotective in Deoxycorticosterone Acetate-Salt Nephropathy.

Underlying pathogenic mechanisms in chronic kidney disease (CKD) include chronic inflammation, oxidant stress, and matrix remodeling associated with dysregulated NF-ĸB, NRF2 and SMAD signaling pathways, respectively. Important cytoprotective mechanisms activated by oxidative inflammatory conditions are mediated by nitrated fatty acids (NO2-FA) that covalently modify proteins to limit inflammation and oxidant stress. In the present study we evaluated the effects of chronic treatment with CXA-10 (10-nitro-9(E)-octadec-9-enoic acid) in the uni-nephrectomized deoxycorticosterone acetate (DOCA)-high salt mouse model of CKD. After 4 weeks of treatment, CXA-10 (2.5 mpk, p.o.) significantly attenuated increases in plasma cholesterol, heart weight and kidney weight observed in the model without impacting systemic arterial blood pressure. CXA-10 also reduced albuminuria, nephrinuria, glomerular hypertrophy and glomerulosclerosis in the model. Inflammatory (MCP-1) and fibrosis (collagen, fibronectin, PAI-1 and osteopontin) renal biomarkers were significantly reduced in the CXA-10 (2.5 mpk) group. The anti-inflammatory and anti-fibrotic effects, as well as glomerular protection were not observed in the enalapril treated group. Also, CXA-10 appears to exhibit hormesis as all protective effects observed in the low dose group were absent in the high dose group (12.5 mpk). Taken together, these findings demonstrate that at the appropriate dose, the nitrated fatty acid CXA-10 exhibits anti-inflammatory and anti-fibrotic effects in the kidney and limits renal injury in a model of CKD.