Finerenone Reduces Intrinsic Arterial Stiffness in Munich Wistar Frömter Rats, a Genetic Model of Chronic Kidney Disease.

Autor:	Gil-Ortega M; Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain., Vega-Martín E; Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense, Madrid, Spain., Martín-Ramos M; Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense, Madrid, Spain., González-Blázquez R; Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain., Pulido-Olmo H; Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense, Madrid, Spain., Ruiz-Hurtado G; Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre/CIBER-CV, Madrid, Spain.; Departamento de Salud Pública y Medicina Preventiva, Universidad Autónoma de Madrid, Madrid, Spain., Schulz A; Department of Clinical Pharmacology and Toxicology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Ruilope LM; Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre/CIBER-CV, Madrid, Spain.; Departamento de Salud Pública y Medicina Preventiva, Universidad Autónoma de Madrid, Madrid, Spain., Kolkhof P; Bayer AG, Preclinical Research Cardiovascular, Wuppertal, Germany., Somoza B; Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain., Kreutz R; Department of Clinical Pharmacology and Toxicology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, Reinhold.Kreutz@charite.de., Fernández-Alfonso MS; Instituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	American journal of nephrology [Am J Nephrol] 2020; Vol. 51 (4), pp. 294-303. Date of Electronic Publication: 2020 Feb 21.
DOI:	10.1159/000506275
Abstrakt:	Background: Development of albuminuria and arterial stiffness in Munich Wistar Frömter (MWF) rats, a model of chronic kidney disease, is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction. Finerenone (FIN), a novel, nonsteroidal, potent, and selective mineralocorticoid receptor antagonist, improves endothelial dysfunction through enhancing nitric oxide (NO) bioavailability and decreasing superoxide anion levels due to an upregulation in vascular and renal superoxide dismutase activity. We hypothesize that FIN reduces arterial stiffness in this model associated to the reduction in albuminuria and matrix metalloproteinase (MMP)-2/9 activity. Methods: Twelve-week-old MWF rats with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated with FIN (10 mg/kg/day, once-daily oral gavage) or with vehicle (control, C) for 4 weeks. Results: Arterial stiffness was significantly higher in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN treatment significantly lowered β-index, a measure of intrinsic stiffness independent of geometry, in MWF (βMWF-FIN = 7.7 ± 0.4 vs. βMWF-C = 9.2 ± 0.5, p < 0.05) positively correlating with urinary albumin excretion. Elastin fenestrae area in the internal elastic lamina of MA from MWF-FIN was significantly larger (+377%, p < 0.05). FIN increased plasma pro-MMP-2 and decreased plasma MMP-2 and MMP-9 activities, correlating with reductions in β-index. MA from MWF-FIN exhibited higher NO bioavailability and reduced superoxide anion levels compared to MWF-C. Conclusion: FIN treatment reduces intrinsic arterial stiffness in MA from MWF rats associated with changes in elastin organization, normalization of MMP-2 and MMP-9 activities, and reduction of oxidative stress. Moreover, reduction of arterial stiffness correlates with reduction in albuminuria. (© 2020 S. Karger AG, Basel.)
Databáze:	MEDLINE
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