title: Protective cardiorenal effects of spironolactone in a rodent model of polycystic kidney disease.
abstract: Studies were performed to examine the contribution of aldosterone to the pathogenesis of cardiovascular and renal disease in a rodent model of genetic kidney disease. Spironolactone (20 mg/kg per day) was administered in water to mixed sex Lewis Polycystic Kidney (LPK) rats (n = 20) and control Lewis rats (n = 27) from 4 to 12 weeks of age. At 12 weeks of age, hypertension was reduced in female LPK rats; systolic blood pressure declined from 226.4 ± 26.8 mmHg in untreated rats and to 179.2 ± 3.2 mmHg in treated rats (P = 0.018). No similar effect on male or control rats was found. Water consumption and urine volume were significantly greater in LPK animals than in Lewis rats, and treatment reduced both variables by ~30% in LPK animals (P < 0.05). Proteinuria and the urinary protein-to-creatinine ratio were normalized in treated LPK relative to Lewis controls, and plasma creatinine levels were significantly reduced by treatment in LPK rats. Spironolactone did not alter kidney morphology in LPK rats (fibrosis or cyst size). Aortic vascular responses to noradrenaline and acetylcholine were sensitized and impaired in the LPK (P < 0.01). Aldosterone antagonism did not alter these responses or indicators of aortic structural remodelling. There was no treatment effect on left ventricular hypertrophy or elevated cardiac messenger RNA for β-myosin-heavy chain and brain natriuretic peptide in the LPK rats. However, perivascular fibrosis and messenger RNA for α-cardiac actin were normalized by spironolactone in LPK animals relative to Lewis controls. In conclusion, we have shown an important blood pressure independent effect whereby inhibition of aldosterone via spironolactone was able to retard both renal and cardiac disease progression in a rodent model of polycystic kidney disease.
authors: Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors: Thamarasee M
authors: TM
authors: Jeewandara
authors: Omar Z
authors: OZ
authors: Ameer
authors: Rochelle
authors: R
authors: Boyd
authors: Benjamin F
authors: BF
authors: Wyse
authors: Conor F
authors: CF
authors: Underwood
authors: Jacqueline K
authors: JK
authors: Phillips
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D007690:Polycystic Kidney Diseases / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011917:Rats, Inbred Lew; D012737:Sex Factors; D013148:Spironolactone / Q000494:pharmacology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone
keywords: aldosterone; fibrosis; hypertension; left ventricular hypertrophy; polycystic kidney disease; vascular