*Article* **Activation of RAAS Signaling Contributes to Hypertension in Aged** *Hyp* **Mice**

**Nejla Latic, Ana Zupcic, Danny Frauenstein and Reinhold G. Erben \***

Department of Biomedical Sciences, University of Veterinary Medicine, Veterinaerplatz 1, 1210 Vienna, Austria; nejla.latic@vetmeduni.ac.at (N.L.); ana.zupcic@vetmeduni.ac.at (A.Z.); danny.frauenstein@gmail.com (D.F.) **\*** Correspondence: reinhold.erben@vetmeduni.ac.at; Tel.: +43-1-250-77-4550

**Abstract:** High circulating levels of fibroblast growth factor-23 (FGF23) are associated with left ventricular hypertrophy as well as increased morbidity and mortality in patients suffering from chronic kidney disease. However, the mechanisms underlying this association are controversial. Here, we aimed to further characterize the cardiovascular sequelae of long term endogenous FGF23 hypersecretion using 14-month-old male *Hyp* mice as a model of FGF23 excess. *Hyp* mice were characterized by a ~10-fold increase in circulating intact FGF23, hypophosphatemia, increased serum aldosterone, but normal kidney function, relative to wildtype (WT) controls. Cardiovascular phenotyping did not reveal any evidence of left ventricular hypertrophy or functional impairment in 14-month-old *Hyp* mice. Fractional shortening, ejection fraction, molecular markers of hypertrophy (*Anp*, *Bnp*), and intracardiac markers of contractility and diastolic function were all unchanged in these animals. However, intraarterial catheterization revealed an increase in systolic, diastolic, and mean arterial pressure of ~12 mm Hg in aged *Hyp* mice relative to WT controls. Hypertension in *Hyp* mice was associated with increased peripheral vascular resistance. To test the hypothesis that a stimulation of the renin–angiotensin–aldosterone system (RAAS) contributes to hypertension in aged *Hyp* mice, we administered the angiotensin receptor blocker losartan (30 mg/kg twice daily) or the mineralocorticoid receptor antagonist canrenone (30 mg/kg once daily) to aged *Hyp* and WT mice over 5 days. Both drugs had minor effects on blood pressure in WT mice, but reduced blood pressure and peripheral vascular resistance in *Hyp* mice, suggesting that a stimulation of the RAAS contributes to hypertension in aged *Hyp* mice.

**Keywords:** fibroblast growth factor-23; left ventricular hypertrophy; hypertension; renin–angiotensin– aldosterone system; losartan; canrenone; *Hyp* mice; X-linked hypophosphatemia
