Aldosterone-and-salt-induced cardiac fibrosis is independent from angiotensin II type 1a receptor signaling in mice

Aldosterone infusion with high salt treatment induces cardiac fibrosis in rats. Aldosterone enhanced angiotensin II (Ang II) has been shown to induce proliferation and increase the expression of Ang II receptor mRNA and Ang II binding in vitro. To investigate the role of Ang II type la receptor (AT1aR) in aldosterone-and-salt (Ald-NaCl)-induced cardiac fibrosis, we subcutaneously infused aldosterone (0.15 mu g/h) and 1% NaCl (AId-NaCI) into AT1aR knockout mice (AT1aR-KO) or wild type mice (Wt). To examine the role of NaCl on cardiac fibrosis, we gave some of the aldosterone-treated AT1aR-KO tap water (AId-H2O). Aid-NaCl treatment increased systolic blood pressure and induced cardiac hypertrophy in both strains, whereas there were no such changes in the mice without aldosterone. Severe cardiac fibrosis was seen in AId-NaCI-treated AT1aR-KO and not in AId-NaCI-treated Wt. In contrast, Aid-NaCl-treated Wt with co-administration of an active metabolite of olmesartan, the AT1aR antagonist (10 mg/kg/day) did not show cardiac fibrosis. Na+/H+ exchanger, and Na+-K+ ATPase alpha 2 subunit mRNA were decreased in AT1aR-KO. Na+/Ca2+ exchanger mRNA was lower in AT1aR-KO than Wt and was decreased by AId-NaCI in both strains. Phosphorylation of epidermal growth factor receptor and extracellular signal-regulated kinase was increased by Aid-NaCl treatment in AT1aR-KO. Connective tissue growth factor (CTGF) and osteopontin mRNA were increased and accumulation of CTGF proteins was seen in the hearts of AId-NaCI-treated AT1aR-KO. AId-H2O-treated AT1aR-KO did not show any cardiac fibrosis. These results suggest that AId-NaCI-induced cardiac fibrosis required both aldosterone and salt. Because cardiac fibrosis was exaggerated in AId-NaCI-treated AT1aR-KO but was not seen in Wt treated with Aid-NaCl and olmesartan, AT1aR may not play a primary role in progression of cardiac fibrosis by Aid-NaCl, and gene disruption of AT1aR may have some implications in this model.