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Abstract: TH-PO374

Additive Renoprotective Effects of Angiotensin Converting Enzyme Inhibition and Nitro Fatty Acid (CXA-10) Combination

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Polichnowski, Aaron J., East Tennessee State University, Johnson City, Tennessee, United States
  • Bidani, Anil K., Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
  • Williamson, Geoffrey A., Illinois Institute of Technology, Chicago, Illinois, United States
  • Finman, Jeffrey S., Complexa, Inc., Berwyn, Pennsylvania, United States
  • Mcalexander, Michael, Complexa, Inc., Berwyn, Pennsylvania, United States
  • Griffin, Karen A., Loyola University Medical Center Hines VA Hospital, Maywood, Illinois, United States
  • Willette, Robert N., Complexa, Inc., Berwyn, Pennsylvania, United States
  • Jorkasky, Diane K., Complexa, Inc., Berwyn, Pennsylvania, United States
Background

Underlying pathogenic mechanisms in chronic kidney disease (CKD) include chronic inflammation, oxidant stress, and matrix remodeling associated with dysregulated NF-κB, NRF2 and SMAD signaling pathways, respectively. During CKD progression these pathogenic mechanisms overwhelm endogenous cytoprotective mechanisms mediated by nitro fatty acids (NO2-FA) that act through posttranslational protein modification to limit inflammation and oxidant stress.

Methods

To restore cytoprotective balance, we evaluated the effects of chronic treatment with CXA-10 (10-nitro-9(E)-octadec-9-enoic acid), a nitro fatty acid, in a reduced renal mass (RRM) – high salt rat model of progressive CKD. Five treatment groups were examined (Control, CXA-10 (1.25 and 3.75 mg/kg, p.o.), enalapril and enalapril + CXA-10), for a 3-week dosing period that commenced 4 weeks following RRM.

Results

Enalapril significantly attenuated the increase in mean arterial pressure (MAP) and mildly blunted proteinuria, non-significantly. Similarly, the low dose of CXA-10 non-significantly attenuated proteinuria but had no effect on the increase in MAP. In a two-factor analysis model, both CXA-10 and enalapril treatment significantly blunted the increase in proteinuria (p= 0.048 and 0.045, respectively). The combination of enalapril and CXA-10 (1.25 mg/kg) did not further alter MAP more than enalapril alone, but significantly reduce proteinuria after 3 weeks of treatment when compared to Control (-12% vs. 30%). Treatment with CXA-10 alone (1.25mg/kg & 3.75 mg/kg) maintained renal blood flow (RBF) at pretreatment levels. Based on a histopathologic analysis, none of these short-term treatment regimens (3 weeks) altered the moderate glomerulosclerosis and mild renovascular injury observed in the model.

Conclusion

The results suggest that the combination of enalapril and CXA-10 may exert additive MAP-dependent (enalapril) and MAP-independent (CXA-10) effects to limit increases in proteinuria without compromising renal perfusion.

Funding

  • Commercial Support