Kidney Week

Abstract: SA-PO352

Normalization of Matrix Metalloproteinase Activity and Elastin Structure by Finerenone Reduces Arterial Stiffness in Mesenteric Resistance Arteries in a Rat Model of CKD

Session Information

• Hypertension and CVD: Mechanisms
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Authors

• Fernandez-Alfonso, Maria S., Universidad Complutense de Madrid, Madrid, Spain

Maria S. Fernandez-Alfonso,

• Gil-Ortega, Marta, San Pablo CE University, Alcorcón, Spain

Marta Gil-Ortega,

• Vega martín, Elena, Facultad de Farmacia, Madrid, Spain

Elena Vega martín,

• Blázquez, Raquel González, San Pablo Ceu University, Madrid, Spain

Raquel González Blázquez,

• Ruiz-Hurtado, Gema, Hospital Universitario 12 de Octubre, Madrid, Spain

Gema Ruiz-Hurtado,

• Schulz, Angela, Charité - Universitätsmedizin Berlin, Berlin, Germany

Angela Schulz,

• Ruilope, Luis M., National Instituto of Health, Spain, Madrid, Spain

Luis M. Ruilope,

• Kolkhof, Peter, Bayer AG, Wuppertal, Germany

Peter Kolkhof,

• Somoza, Beatriz, San Pablo CE University, Alcorcón, Spain

Beatriz Somoza,

• Kreutz, Reinhold, Charité - Universitätsmedizin Berlin, Berlin, Germany

Reinhold Kreutz,

Background

Both albuminuria and arterial stiffness are independent predictors of cardiovascular morbidity and mortality associated to the progression of chronic kidney disease (CKD). This association supports a potential generalized vascular dysfunction with similar pathophysiologic mechanisms linking the cardiovascular-renal axis in patients with albuminuria. We aim to explore the effect of the mineralocorticoid receptor antagonist, finerenone (FIN), on vascular mechanics and structure in 2^nd branch mesenteric resistance arteries (MA) from Munich Wistar Fromter (MWF) rats, a genetic model of non-diabetic CKD.

Methods

Wistar (W) and MWF rats were randomly grouped (n=10 per group) to receive either 10 mg/kg/day FIN (W-FIN; MWF-FIN) or vehicle (W-C; MWF-C) for 4 weeks by oral gavage. Mechanical and structural properties of MA were determined by pressure myography. Elastin organization in the internal elastic lamina (IEL) was analysed by confocal microscopy based on elastin autofluorescence. Metalloproteinase activity was assessed by gelatin zymography.

Results

FIN led to a significant reduction (>40%) in albuminuria in MWF. The stress/strain relationship curve in MA from MWF-FIN exhibited a significant right-shift, indicative of lower intrinsic arterial stiffness. No changes were observed in structural parameters (external and internal diameter, wall-to-lumen ratio, cross-sectional area and adventitial, medial and wall thickness) of MA. IEL from MWF-C animals showed significantly smaller fenestrae than W-C, without changes in total number of fenestrae. FIN significantly reduced fenestrae number in both W-FIN and MWF-FIN, and increased fenestrae area in MWF-FIN. Pro-MMP-2 activity was significantly lower in plasma samples from MWF-C rats compared with W-C rats, paralleled by higher levels of active MMP-2 and MMP-9 activities. FIN restored pro-MMP-2, MMP-2 and MMP-9 activities in MWF to control levels.

Conclusion

This study demonstrates the efficacy of FIN to ameliorate albuminuria and normalize circulating MMP activities, elastin structure and intrinsic arterial stiffness in MA from MWF rats.

Funding

• Commercial Support – Bayer AG (Germany)