Altered renal function and the development of angiotensin II-dependent hypertension

Abstract

Inappropriate modulation of the renin angiotensin system (RAS) can lead to derangements of blood pressure homeostasis in humans. Cyp1a1-mRen2.F transgenic rats were used to define the renal mechanisms underlying the development of angiotensin II-dependent hypertension. These transgenic rats were previously generated by introducing the mouse Ren2 gene into the rat genome under the control of a Cyp1a1 inducible promoter. The aim of the current investigation was to establish the contribution of renal function to the development of hypertension in the Cyp1a1- mRen2.F transgenic rat. Expression of the mRen2 transgene was induced by daily gavage of indole 3 carbinol (I3C) at the dose of 100mg/kg. Blood pressure was measured in conscious rats after 1, 3 or 7 days of treatment. The control group received the vegetable oil carrier for 7 days. In addition blood pressure, renal haemodynamics and excretory function were measured under thiobutabarbital anaesthesia. Transgene induction caused a progressive increase in blood pressure in a time dependent manner. Neither glomerular filtration rate nor renal blood flow was affected. This indicates proper function of renal autoregulation during the experimental time course. Tubular sodium reabsorption was significantly increased after the first day of transgene induction and this effect was sustained for the duration of treatment. A pharmacological approach was used to localize the increased reabsorption to a specific region of the nephron and was found to reflect increased activity of the thiazide-sensitive cotransporter (NCC). Chronic administration of thiazide significantly blunted the hypertensive response to transgene induction. Similarly AT1 receptor blockade attenuated the hypertensive phenotype and prevented the transgene-induced stimulation of NCC activity. In contrast, mineralocorticoid receptor blockade did not prevent the development of either hypertension or increased NCC activity. The current study suggests that the development of angiotensin II-dependent hypertension is mediated by increased tubular sodium reabsorption. Increased activity of NCC is a key hypertensive mechanism in this model and results directly from the actions of angiotensin II at the AT1 receptor; indirect aldosterone pathways do not play a major role.