title: Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat.
abstract: Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP) rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ≈ 20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ali
authors.initials: A
authors.lastname: Ashek
authors.forename: Robert I
authors.initials: RI
authors.lastname: Menzies
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Mullins
authors.forename: Christopher O C
authors.initials: CO
authors.lastname: Bellamy
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Harmar
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.forename: Peter W
authors.initials: PW
authors.lastname: Flatman
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007686:Kidney Tubules, Distal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics*; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; C535029:Ren2 protein, rat; D049992:Sodium Chloride Symporters; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D013148:Spironolactone; D019363:Cytochrome P-450 CYP1A1; D012083:Renin; D019808:Losartan