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

Autor:	Arbeeny CM; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., Ling H; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., Smith MM; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., O'Brien S; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., Wawersik S; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., Ledbetter SR; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., McAlexander A; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., Schopfer FJ; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., Willette RN; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.)., Jorkasky DK; Sanofi, Framingham (C.M.A., M.M.S., S.R.L.), Novartis (H.L., S.O.) and Scholar Rock (S.W.), Cambridge, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania (F.J.S) and Complexa, Inc., Berwyn, Pennsylvania (A.M., R.N.W., D.K.J.) Diane.jorkasky@complexarx.com.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 Jun; Vol. 369 (3), pp. 503-510. Date of Electronic Publication: 2019 Mar 20.
DOI:	10.1124/jpet.118.254755
Abstrakt:	Underlying pathogenic mechanisms in chronic kidney disease (CKD) include chronic inflammation, oxidant stress, and matrix remodeling associated with dysregulated nuclear factor- κ B, nuclear factor- κ B, and SMAD signaling pathways, respectively. Important cytoprotective mechanisms activated by oxidative inflammatory conditions are mediated by nitrated fatty acids 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 uninephrectomized deoxycorticosterone acetate-high-salt mouse model of CKD. After 4 weeks of treatment, CXA-10 [2.5 millligrams per kilogram (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, plasminogen activator inhibitor-1, and osteopontin) renal biomarkers were significantly reduced in the CXA-10 (2.5 mpk) group. The anti-inflammatory and antifibrotic 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 antifibrotic effects in the kidney and limits renal injury in a model of CKD. (Copyright © 2019 The Author(s).)
Databáze:	MEDLINE
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