Abstract
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.
Highlights
The Renin-angiotensin (RA) system has been implicated in essential hypertension because of the antihypertensive effects of RA system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II receptor blockers (ARBs)
We have demonstrated that the formation of Endothelial progenitor cells (EPCs) is suppressed in salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) with increases in oxidative stress and that treatment with ARBs improved the suppression of EPC formation [8,9]
Salt-loaded SHRs were randomly divided into 4 groups: rats treated with vehicle (SHR-V, n=9), rats treated with hydralazine (120 mg/l, drinking water; SHR-H, n=8), rats treated with olmesartan medoxomil (Daiichi Sankyo, 0.5 mg/kg per day PO; SHR-O, n=8), and rats treated with olmesartan medoxomil and MasR antagonist A779 (0.5 mg/kg per day PO; SHROA, n=7) for 2 weeks
Summary
The Renin-angiotensin (RA) system has been implicated in essential hypertension because of the antihypertensive effects of RA system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II receptor blockers (ARBs). ARBs have improvement effects on impaired endothelial function by Ang II-mediated oxidative stress in hypertension [5,6]. Endothelial progenitor cells (EPCs) derived from bone marrow represent up to 0.01% of cells in the peripheral blood. These cells migrate to areas of endothelial damage and repair them, suggesting that EPC dysfunction determines the eventual level of vascular injury [7]. It has been demonstrated that oxidative stress induces endothelial damage by shortening EPC life span and causing EPC dysfunction [8]. We have demonstrated that the formation of EPCs is suppressed in salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) with increases in oxidative stress and that treatment with ARBs (losartan, candesartan, and valsartan) improved the suppression of EPC formation [8,9]. How and where ARB affects EPCs to improve their formation, has been unclear
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