Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency

摘要

We studied whether endothelin receptor antagonist and calcimimetic treatments influence renal damage and kidney renin-angiotensin (RA) components in adenine-induced chronic renal insufficiency (CRI). Male Wistar rats (n?=?80) were divided into 5 groups for 12?weeks: control (n?=?12), 0.3% adenine (Ade; n?=?20), Ade?+?50?mg/kg/day sitaxentan (n?=?16), Ade?+?20?mg/kg/day cinacalcet (n?=?16), and Ade?+?sitaxentan?+?cinacalcet (n?=?16). Blood pressure (BP) was measured using tail-cuff, kidney histology was examined, and RA components measured using RT-qPCR. Adenine caused tubulointerstitial damage with severe CRI, anemia, hyperphosphatemia, 1.8-fold increase in urinary calcium excretion, and 3.5-fold and 18-fold increases in plasma creatinine and PTH, respectively. Sitaxentan alleviated tubular atrophy, while sitaxentan?+?cinacalcet combination reduced interstitial inflammation, tubular dilatation and atrophy in adenine-rats. Adenine diet did not influence kidney angiotensin converting enzyme (ACE) and AT4 receptor mRNA, but reduced mRNA of renin, AT1a, AT2, (pro)renin receptor and Mas to 40–60%, and suppressed ACE2 to 6% of that in controls. Sitaxentan reduced BP by 8?mmHg, creatinine, urea, and phosphate concentrations by 16–24%, and PTH by 42%. Cinacalcet did not influence BP or creatinine, but reduced PTH by 84%, and increased hemoglobin by 28% in adenine-rats. The treatments further reduced renin mRNA by 40%, while combined treatment normalized plasma PTH, urinary calcium, and increased ACE2 mRNA 2.5-fold versus the Ade group (p?