Relaxin Attenuates Organ Fibrosis via an Angiotensin Type 2 Receptor Mechanism in Aged Hypertensive Female Rats
Giannie Barsha, Sarah L. Walton, Edmund Kwok, Katrina M. Mirabito Colafella, Anita A. Pinar, Lucinda M. Hilliard Krause, Tracey A. Gaspari, Robert E. Widdop, Chrishan S. Samuel, Kate M. Denton
Abstract
Key Points Relaxin attenuates tissue fibrosis in an organ- and age-specific manner. The antifibrotic actions of relaxin are mediated via an angiotensin type 2 receptor mechanism. Relaxin replacement therapy is a potential antifibrotic for cardiovascular and kidney disease in postmenopausal women. Background The antifibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT 2 R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via AT 2 R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection via an AT 2 R-dependent mechanism in adult and aged female stroke-prone spontaneously hypertensive rats (SHRSPs). Methods In 6-month-old (6MO) and 15-month-old ([15MO]; reproductively senescent) female SHRSP, systolic BP (SBP), GFR, and proteinuria were measured before and after 4 weeks of treatment with vehicle (Veh), RLX (0.5 mg/kg per day s.c.), or RLX+PD123319 (AT 2 R antagonist; 3 mg/kg per day s.c.). Aortic endothelium–dependent relaxation and fibrosis of the kidney, heart, and aorta were assessed. Results In 6MO SHRSP, RLX significantly enhanced GFR by approximately 25% ( P =0.001) and reduced cardiac fibrosis ( P =0.01) as compared with vehicle-treated counterparts. These effects were abolished or blunted by PD123319 coadministration. In 15MO females, RLX reduced interstitial renal ( P =0.02) and aortic ( P =0.003) fibrosis and lowered SBP (13±3 mm Hg; P =0.04) relative to controls. These effects were also blocked by PD123319 cotreatment (all P =0.05 versus RLX treatment alone). RLX also markedly improved vascular function by approximately 40% ( P <0.001) in 15MO SHRSP, but this was not modulated by PD123319 cotreatment. Conclusions The antifibrotic and organ-protective effects of RLX, when administered to a severe model of hypertension, conferred cardiorenal protection in adult and reproductively senescent female rats to a great extent via an AT 2 R-mediated mechanism.