Genetic clamping of renin gene expression induces hypertension and elevation of intrarenal Ang II levels of graded severity in Cyp1a1-Ren2 transgenic rats.
BACKGROUND
Transgenic rats with inducible angiotensin II (Ang II)-dependent hypertension (strain name: TGR[Cyp1a1-Ren2]) were generated by inserting the mouse Ren2 renin gene, fused to the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the rat. The present study was performed to characterise the changes in plasma and kidney tissue Ang II levels and in renal haemodynamic function in Cyp1a1-Ren2 rats following induction of either slowly developing or malignant hypertension in these transgenic rats.


METHODS
Arterial blood pressure (BP) and renal haemodynamics and excretory function were measured in pentobarbital sodium-anaesthetised Cyp1a1- Ren2 rats fed a normal diet containing either a low dose (0.15%, w/w for 1415 days) or high dose (0.3%, w/w for 1112 days) of the aryl hydrocarbon indole-3-carbinol (I3C) to induce slowly developing and malignant hypertension, respectively. In parallel experiments, arterial blood samples and kidneys were harvested for measurement of Ang II levels by radioimmunoassay.


RESULTS
Dietary I3C increased plasma renin activity (PRA), plasma Ang II levels, and arterial BP in a dose-dependent manner. Induction of different fixed levels of renin gene expression and PRA produced hypertensive phenotypes of varying severity with rats developing either mild or malignant forms of hypertensive disease. Administration of I3C, at a dose of 0.15% (w/w), induced a slowly developing form of hypertension whereas administration of a higher dose (0.3%) induced a more rapidly developing hypertension and the clinical manifestations of malignant hypertension including severe weight loss. Both hypertensive phenotypes were characterised by reduced renal plasma flow, increased filtration fraction, elevated PRA, and increased plasma and intrarenal Ang II levels. These I3C-induced changes in renal haemodynamics, PRA and kidney Ang II levels were more pronounced in Cyp1a1-Ren2 rats with malignant hypertension. Chronic administration of the AT1-receptor antagonist, hypertension, the associated changes in renal haemodynamics, and the augmentation of intrarenal Ang II levels.


CONCLUSIONS
Activation of AT1-receptors by Ang II generated as a consequence of induction of the Cyp1a1-Ren2 transgene mediates the increased arterial pressure and the associated reduction of renal haemodynamics and enhancement of intrarenal Ang II levels in hypertensive Cyp1a1-Ren2 transgenic rats.
Mitchell
Kenneth D
KD
Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA. kdmitch@tulane.edu
Bagatell
Stuart J
SJ
Miller
Chad S
CS
Mouton
Cynthia R
CR
Seth
Dale M
DM
Mullins
John J
JJ
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D030801:Animals, Genetically Modified; D015870:Gene Expression; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007211:Indoles; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D007211:Indoles; D044140:Receptor, Angiotensin, Type 1; C473112:Ren2 protein, mouse; D000804:Angiotensin II; C016517:indole-3-carbinol; D012083:Renin