title: Role of angiotensin-converting enzyme 2 and angiotensin(1-7) in 17beta-oestradiol regulation of renal pathology in renal wrap hypertension in rats.
abstract: 17beta-Oestradiol (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 catalysing 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 in rats. After 6 weeks on a high-sodium diet (4% NaCl), the activity of ACE2 was reduced in the renal cortex by 31%, which was mirrored by similar decreases in ACE2 protein (30%) and mRNA expression (36%) in the ovariectomized RW rat (RW-OVX); E2 replacement prevented these effects. The 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 and RW-OVX+E2). Angiotensin(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 rats. These renal protective effects of Ang(1-7) infusion were not attributable to increased ACE2 activity or to changes in heart rate or body weight, 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 during a 6 week chronic treatment for Ang(1-7). These results suggest that E2-mediated upregulation of renal ACE2 and the consequent increased Ang(1-7) production contribute 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.
authors.affiliation: Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, DC, USA. jih@georgetown.edu
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Stefano
authors.initials: S
authors.lastname: Menini
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Carlo
authors.initials: C
authors.lastname: Pesce
authors.forename: Xie
authors.initials: X
authors.lastname: Wu
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sandberg
mesh_terms: D000803:Angiotensin I / Q000502:physiology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D004958:Estradiol / Q000502:physiology*; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006978:Hypertension, Renovascular / Q000378:metabolism* / Q000473:pathology*; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D010052:Ovariectomy; D010446:Peptide Fragments / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; D004958:Estradiol; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)