FINERENONE REDUCES INTRINSIC ARTERIAL STIFFNESS IN A HYPERTENISVE NON-DIABETIC RAT MODEL OF CHRONIC KIDNEY DISEASE

Abstract

Objective: Albuminuria development and arterial stiffness is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction in Munich Wistar Frömter (MWF) rats, a non-diabetic model of chronic kidney disease. We tested whether finerenone (FIN), a next-generation, oral, selective, and non-steroidal mineralocorticoid receptor antagonist, reduces arterial stiffness in this model. Design and method: Twelve-week-old MWF with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated for 4-weeks with FIN (10 mg/kg/day, once daily oral gavage) or with vehicle (control, C). Results: Intrinsic arterial stiffness is significantly increased in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN significantly lowered this phenotype in MWF-FIN compared to MWF-C, as observed from the lower βvalues obtained from the stress-strain relationship curve (βMWF-FIN = 7.7 ± 0.4 vs βMWF-C = 9.2 ± 0.5, p < 0.05). FIN also improved endothelial function in MA of MWF-FIN compared to MWF-C through an increase in nitric oxide bioavailability and a reduction in superoxide anion and hydrogen peroxide levels. Of interest, FIN led to an increase in fenestrae's area in the internal elastic lamina (+377%, p < 0.05). This was associated to a decrease in plasma MMP-2 and MMP-9 activity. Conclusions: FIN significantly reduces intrinsic arterial stiffness in MA from MWF rats. This is related to the enlargement of elastin fenestrae area, which may allow a better diffusion from endothelial factors to the underlying smooth muscle layer thereby improving endothelial function.