Abstract 043: Targeting the Angiotensin Type 2 Receptor With Relaxin Confers Protection Against Renal Fibrosis and Vascular Dysfunction in Female Stroke Prone-Spontaneously Hypertensive Rats

Abstract

The angiotensin type 2 receptor (AT 2 R) mediates cardiovascular and renal protection in females of reproductive age, a mechanism that is lost with advancing age. Recently, we demonstrated that the nitric oxide-promoting and transforming growth factor-β1 inhibitory actions of relaxin (RLX) involve an interaction between the relaxin-insulin like family peptide receptor 1 (RXFP1) and the AT 2 R. In the present study, we aimed to determine whether RLX induces cardio-renal protection and slows the progression of end-organ damage, via an AT 2 R-dependent mechanism. In female stroke prone-spontaneously hypertensive rats (SP-SHR) at 6 (young) and 14-15 (aged reproductively senescent) months of age arterial pressure, cardiac function, glomerular filtration rate (GFR) and proteinuria were measured before and after 4 weeks of treatment with vehicle (sodium acetate s.c.), RLX (serelaxin; 0.5mg/kg/day s.c.) or RLX+PD123319 (AT 2 R antagonist; 3mg/kg/day s.c). In addition, aortic endothelium-dependent relaxation in response to acetylcholine was assessed and cardiac and renal tissues were histologically analyzed for fibrosis. An age-related decline in GFR and increases in arterial pressure, proteinuria and cardiac and renal fibrosis were observed (all P<0.05; n=4-8). RLX treatment had no significant effect on these variables in the aged group. However, in aged animals, RLX markedly improved endothelial function (~30% increase in maximal vasodilation as compared to vehicle counterparts, P=0.0002; n=4-6). This effect was partially reversed by co-infusion with PD123319, relative to RLX alone (~14% reduced maximal vasodilation, P=0.03; n=6). In young females, RLX+PD123319 as compared to RLX treatment alone, exacerbated glomerular (11.6±1.2% vs 8.5±0.7%, respectively, P=0.04) and tubulointerstitial (3.3±0.2% vs 1.6±0.2%, respectively, P=0.0002) fibrosis. In conclusion, the cardio-renal protective actions of relaxin are dependent in part, upon an interaction with the AT 2 R. Thus, targeting the RXFP1-AT 2 R axis may be a therapeutic option for the treatment of cardiovascular disease and associated end-organ damage in hypertensive women.