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Transient renin–angiotensin system stimulation in an early stage of life causes sustained hypertension in rats

Objectives Transient administration of inhibitors of the renin–angiotensin system (RAS) during the prehypertensive period in rats and humans leads to a long-lasting lowering of blood pressure (BP). Our aim was to unravel the critical period in which activation of the RAS induces chronic effects on BP and to determine the role of renal function and structure in this process. Methods Studies were performed in Cyp1a1-Ren2 rats, which harbor a construct for the production of mouse renin. This construct becomes activated when indole-3-carbinol (I3C) is added to the diet. Young (4 weeks old) and adult (30 weeks old) Cyp1a1-Ren2 rats were randomly assigned to either the I3C treatment group or the control group. Renin production was stimulated from week 4 to 8 in young and week 30 to 34 in adult rats. BP follow-up was performed via photoelectric/oscillometric tail cuff method and intra-arterial BP was determined at 4, 8, 12 and 20 weeks of age or 34 and 38 weeks of age. Additionally, renal vascular resistance, albuminuria, renal inflammation and renal pathology were determined. Results Up to 20 weeks of age, that is, 12 weeks after I3C withdrawal, mean arterial pressure (MAP) was significantly elevated in young I3C-treated rats (141 ± 7 mmHg) compared with controls (125 ± 6 mmHg). In adult rats, renin stimulation caused only a transient elevation in MAP, which returned to control values after I3C withdrawal. In young rats, the sustained pressor response was associated with increased indices of renal vascular resistance, glomerulosclerosis and tubulointerstitial damage as well as with a moderate inflammatory response. In adult rats, renal pathology and inflammation was significantly less than in young rats and was reversible. Conclusion Transient RAS stimulation causes sustained elevation in BP in young, but not in adult Cyp1a1-Ren2 transgenic rats and is associated with irreversible changes in renal structure and function and a moderate renal inflammatory response.