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

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Törmänen , S , Pörsti , I , Lakkisto , P , Tikkanen , I , Niemelä , O , Paavonen , T , Mustonen , J & Eräranta , A 2017 , ' Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency ' , BMC Nephrology , vol. 18 , 323 . https://doi.org/10.1186/s12882-017-0742-z

Title: Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency
Author: Törmänen, Suvi; Pörsti, Ilkka; Lakkisto, Päivi; Tikkanen, Ilkka; Niemelä, Onni; Paavonen, Timo; Mustonen, Jukka; Eräranta, Arttu
Contributor: University of Helsinki, Medicum
University of Helsinki, Clinicum
Date: 2017-10-27
Language: eng
Number of pages: 13
Belongs to series: BMC Nephrology
ISSN: 1471-2369
URI: http://hdl.handle.net/10138/228548
Abstract: Background: 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). Methods: 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. Results: 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 AT(4) receptor mRNA, but reduced mRNA of renin, AT(1a), AT(2), (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 <0.001). Conclusions: In adenine-induced interstitial nephritis, sitaxentan improved renal function and tubular atrophy. Sitaxentan and cinacalcet reduced kidney renin mRNA by 40%, while their combination alleviated tubulointerstitial damage and urinary calcium loss, and increased kidney tissue ACE2 mRNA.
Subject: Chronic kidney disease
Sitaxentan
Cinacalcet
Creatinine
Parathyroid hormone
Renal renin-angiotensin system
CHRONIC KIDNEY-DISEASE
ANGIOTENSIN-CONVERTING ENZYME
TO-MESENCHYMAL TRANSITION
TISSUE-GROWTH-FACTOR
NEPHRECTOMIZED RATS
PARATHYROID-HORMONE
ALDOSTERONE SYSTEM
PHOSPHATE-BINDING
FAILURE
UREMIA
3121 Internal medicine
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