Angiotensin Paradoxically Upregulates a Human Renin Transgene Containing a 900bp Promoter by a Pressure-Independent Mechanism
Renin gene expression is negatively regulated by angiotensin II (AII) and blood pressure (BP). In transgenic mice containing the entire human renin (HREN) gene with only 900 bp of promoter sequence, pressor AII infusion paradoxically increases renal HREN mRNA. Lack of upregulation during subpressor AII suggests that this increase might be mediated by increased BP. To test this hypothesis, the AII-induced increase in BP was prevented by coadministration of the vasodilator, hydralazine (H). AII and H were infused at 1000 ng/kg/min and 15 mg/kg/day, respectively, by osmotic minipump. Isotonic saline was infused as vehicle (V). BP was measured daily by tail cuff, after a 7-day training period and a 5-day baseline period. Renal renin mRNA expression was measured by ribonuclease protection assay (normalized to expression of actin). BP during the last 3 days of a 5 day infusion of AII (n=5) was increased by an average of 37 ± 4 mmHg. There was no significant change in BP in mice infused with V (n=4) or with AII+H (n=4). The level of endogenous mouse renin mRNA was appropriately decreased by about 60% in both AII and AII+H mice relative to V mice. In contrast, HREN mRNA increased almost 2-fold (1.9 ± 0.3) in AII mice compared to V mice. In addition, the normalization of BP in AII+H mice did not prevent the increase in HREN mRNA (2.1 ± 0.3 fold). Thus, renal HREN in transgenic mice containing the entire HREN gene with 900 bp of promoter sequence is increased by pressor AII even when the BP increase is ameliorated by H, suggesting that the upregulation may be due to a direct effect of AII. Moreover, the finding from our previous study of a lack of upregulation during subpressor AII infusion may indicate that this action of AII is dose-dependent. We are currently performing similar studies in transgenic mice containing a well regulated HREN transgene to further elucidate the molecular mechanisms of renin gene regulation and to better understand the defect existing in the present model.