Received November 13, 2007
Revised December 7, 2007
Accepted after revision February 7, 2008

¹ Georgetown University
² Università di Genova

^* To whom correspondence should be addressed. E-mail: jih{at}georgetown.edu.

	Abstract

17-estradiol (E2) mediated inhibition of angiotensin converting enzyme (ACE) protects the E2 replete kidney from the progression of hypertensive renal disease. Angiotensin converting enzyme 2 (ACE2), a homologue of ACE, counters the actions of ACE by catalyzing the conversion of angiotensin II (Ang II) to angiotensin-(1-7) (Ang-(1-7)). We investigated E2 regulation of ACE2 in the renal wrap (RW) model of hypertension. After 6 weeks on a high sodium (4% NaCl) diet, the activity of ACE2 was reduced in the renal cortex by 31%, which was mirrored by similar decreases in ACE2 protein (30%) and mRNA (36%) expression in the ovariectomized RW rat (RW-OVX); E2 replacement prevented these effects. RW-OVX rats exhibited greater renal injury including 1.7-fold more tubulointerstitial fibrosis and 1.6-fold more glomerulosclerosis than E2 replete females (RW-Intact & RW-OVX+E2). Ang-(1-7) infusion prevented these exacerbating effects of ovariectomy on renal pathology; no differences in indicators of renal injury were observed between RW-OVX-Ang-(1-7) and RW-Intact. These renal protective effects of Ang-(1-7) infusion were not attributable to increased ACE2 activity nor to changes in heart rate (HR) or body weight (BW) since these parameters were unchanged by Ang-(1-7) infusion. Furthermore, Ang-(1-7) infusion did not attenuate renal injury by reducing mean arterial pressure (MAP) since infusion of the peptide did not lower MAP but rather caused a slight increase 4 weeks after chronic treatment. These results suggest that E2-mediated up regulation of renal ACE2 and the consequent increased Ang-(1-7) production contributes to E2-mediated protection from hypertensive renal disease. These findings have implications for E2 deficient women with hypertensive renal disease and suggest that therapeutics targeted towards increasing ACE2 activity and Ang-(1-7) levels will be renal protective.

Key Words: Hypertension, Oestrogen, Renal

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