Journal of Hypertension: Open Access

Olmesartan Improves the Formation of Impaired Epcs and Renal Degeneration through Activation of the ACE2/Ang-(1–7)/Mas Receptor Axis in Shrs

Abstract

Noboru Fukuda, Naohiko Kobayashi, Akihiko Nagase, Ryo Suzuki, Takahiro Ueno, and Toshihiko Ishimitsu

Objective: We investigated the effects of angiotensin II (Ang II) type 1 (AT1) receptor blocker (ARB) olmesartan on impaired endothelial progenitor cells (EPCs) and renal degeneration through angiotensin converting enzyme 2 (ACE2)/ Ang-(1–7)/Mas receptor (MasR) axis in salt-loaded spontaneously hypertensive rats (SHRs).

Methods: Wistar-Kyoto/Izm (WKY) rats and SHR/Izm were salt-loaded. SHRs were treated with vehicle, hydralazine, olmesartan, and olmesartan plus MasR antagonist A779 for 2 weeks. Peripheral blood mononuclear cells were isolated and subjected to flow cytometric analysis to determine the number of circulating EPCs. To evaluate the mechanisms of effects of olmesartan on renal degeneration, we investigated morphological changes and expression of ACE1, ACE2, MasR, VEGF, eNOS, NAD(P)H oxidases, HIF-1α, CTGF and TGF-β1 proteins in the kidneys.

Results: In SHRs, olmesartan was found to significantly increase EPC number and improve glomerulosclerosis; effects which were blunted with MasR antagonist A779. Expressions of CD34, P-eNOS, ACE2 and MasR proteins were significantly lower in SHR kidneys than in WKY rats. Olmesartan was found to significantly upregulate decreased expression of these proteins, this was blunted with A779. Expressions of VEGF, ACE1, NAD(P)H oxidases, HIF- 1α, CTGF and TGF-β1 were significantly higher in the kidneys of SHRs than in WKY rats. Olmesartan significantly downregulated their increased expression, an effect which was also blunted with A779.

Conclusion: Olmesartan improved impaired EPC formation and renal degeneration through the ACE2/Ang-(1– 7)/MasR axis in salt-loaded SHRs, suggesting that the ACE2/Ang-(1–7)/MasR axis represents a potential target for hypertension.