The Non-Peptide At2-Receptor Agonist Compound 21 Ameliorates Hypertrophy and Fibrosis in Uremia-Associated Cardiomyopathy: 9d.04

During recent years the so-called “kidney-heart-connection” has been increasingly recognised meaning that chronic kidney disease (CKD) is not only consequence but also cause of cardiac disease. The AT2R has been described to act anti-inflammatory and anti-fibrotic. However, up to now a therapeutic use of these features could not be considered due to the lack of a suitable, orally active AT2R-agonist. Such an selective, non-peptide AT2R-agonist termed Compound 21 (C21) was recently synthesised and tested in this study as a treatment to prevent myocardial changes in a rat model of CKD. CKD was induced by subtotal nephrectomy (SNX) in male Wistar rats. The following groups were formed and treated for 12 weeks: Sham (n = 4); SNX (n = 10) and SNX+C21 (0.15 mg/ kg BW/day., n = 10). After 12 weeks, SNX animals showed significantly increased systolic blood pressure (155 ± 5mmHg) and blood creatinine levels (0.7 ± 0.06 mg/dL). C21 administration moderately and not significantly lowered blood pressure (144 ± 3mmHg, p = NS) and creatinine (0.6 ± 0.03 mg/dL). Regarding the heart, chronic uremia caused a significant increase in heart weight (0.4 ± 0.03 vs. 0.3 ± 0.01 g/100 g BW in sham), cardiomyocyte diameter (21 ± 0.4 vs. 17 ± 0.7m), connective tissue fibre content (40 ± 3.6 vs. 13 ± 2.0%/section), collagen I content (148 ± 10 vs. 125 ± 10% vs. GAPDH), IL-6 protein expression (3.2 ± 0.6 vs. 0.2 ± 0.1% vs. GAPDH) and infiltration with macrophages (4.7 ± 0.5 vs. 0.6 ± 0.1cells/section) and lymphocytes (5.5 ± 0.3 vs. 0.7 ± 0.2cells/section). C21 treatment significantly improved all these markers and lowered heart weight by 15%, cardiomyocyte diameter by 16%, connective tissue fibre content by 50%, collagen I by 25%, IL-6 protein expression by 71% and infiltration with macrophages by 78% and lymphocytes by 71%, respectively. Remarkably, C21 was effective in a blood-pressure independent way. Selective AT2 receptor stimulation significantly ameliorated uremic cardiomyopathy in experimental CKD. The AT2 agonist acted through antihypertrophic, anti-fibrotic and anti-inflammatory pathways. The study provides direct insights into the role of the AT2 receptor and introduces a novel approach of pharmacological interference with the RAS in uremic cardiomyopathy.