Endocrine Abstracts

The kidney plays a dominant role in long-term blood pressure (BP) control and electrolyte homeostasis but aldosterone (aldo) responsive molecular pathways in the kidney involved in regulating BP remain poorly understood despite identification of several participant genes. Many human single gene disorders affecting BP have been faithfully reproduced in mice by targeting the corresponding genes. Thus mouse is an excellent model to study molecular pathways underlying hypertension and normal BP control and hypertensive responses to aldo and escape from these.

We have developed an inducible hypertensive mouse model (mDOCA-salt) whereby adult male C57BL/6 mice develop a highly reproducible BP rise (20-25mmHg over 2-3 weeks) dependent on 3 components: (i)aldo excess (750 microgram per kilogram per day) and (ii)high Na⁺ intake (1% in feed, 3x normal) and (iii)reduced nephron number (uninephrectomy). We have now examined the renal gene expression effects of each component treatment alone and full mDOCA-salt treatment across the time course of induction of hypertension using microarrays (7524 mouse gene oligos: HGMP, MRC, UK) hybridised to renal RNA of groups (n=6) of mice (4-6 arrays/group). Permutation t-tests (p<0.01) showed up-/down regulation c.f. controls of:- 126/67 genes with mDOCA-salt treatment: now being confirmed by northern blot, real-time PCR and in situ hybridisation.

During mDOCA-salt hypertension:- (i)expected changes were manifest: down regulation of elements of the renin-angiotensin system, e.g. renin (1.3 fold, p<0.005), and aquaporins (1.5 fold, p<0.05), (ii)responses to glomerular stress and tissue injury were evident: upregulation of collagens e.g. Col1a1 (2.3 fold, p<0.005) after onset of hypertension (iii)intriguing pathways involved in regulation of BP and natriuresis are being revealed and confirmed, e.g. regulation of CYP4a arachadonic acid metabolising enzymes implicating them as involved in pressure natriuresis. This work and ongoing bioinformatic analysis is producing exciting insights into prohypertensive pathways and molecular routes to accompanying renal damage.