Projects per year
Abstract
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.
Original language | English |
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Pages (from-to) | 1781-1792 |
Number of pages | 12 |
Journal | Kidney360 |
Volume | 2 |
Issue number | 11 |
DOIs | |
Publication status | Published - Nov 2021 |
Keywords
- aging
- angiotensin type 2 receptor
- basic science
- cardiovascular system
- females
- fibrosis
- hypertension
- rats
- relaxin
Projects
- 4 Finished
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Unravelling the aetiology of preeclampsia
National Health and Medical Research Council (NHMRC) (Australia)
1/11/16 → 31/07/21
Project: Research
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Understanding the cardio-protective actions of the AT2R in females: Shifting gears between AT1 and AT2 receptor balance of function with relaxin.
Denton, K., Samuel, C., Widdop, R., Hewitson, T. & Pearson, J.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/16 → 31/12/19
Project: Research