We have described a paradoxical upregulation of human renin mRNA in the kidney of transgenic mice containing both human renin and angiotensinogen genes (double transgenic). These mice exhibit hypertension and increased levels of angiotensin II (AII). In contrast, expression of the endogenous mouse renin gene decreased as expected in response to these stimuli.
In order to explore the mechanism of this response further, transgenic mice containing a human renin genomic construct (single transgenic) with approximately 900 bp of 5' upstream regulatory region were assigned (along with non-transgenic littermates) to receive either chronic AII infusions or control infusions of normal saline via a subcutaneously placed osmotic minipump. Treated animals received 1μg/kg/min of AII. Baseline tail cuff blood pressures were obtained for the 4 days prior to pump placement and for 4 days after recovery from surgery. Plasma was collected for AII measurements, mouse plasma renin activity (mPRA), and human plasma renin concentration(hPRC). AII treated mice had a significant increase in systolic blood pressure from baseline as compared to saline treated controls (+ 32.8 ± 1.4 mm Hg vs -4.1 ± 2.2 mm Hg, p<0.01). Plasma AII levels trended higher in the treated group (147.6 ± 30.3 pg/ml) as compared to controls (120.5± 19.6 pg/ml) but this was not significant. MPRA was appropriately downregulated in response to AII infusion (0.79 ± 0.7 ng AI/ml/hr vs 7.5 ± 2.1 ng AI/ml/hr in controls, p<0.01) while hPRC did not change in treated (36.3 ± 5.8 ng AI/ml/hr) versus control animals (32.5± 2.8 ng AI/ml/hr). RNase protection assay shows upregulation of human renin gene in AII treated animals when compared to controls. This upregulation is similar to that previously seen in double transgenic animals. This paradoxical response to hypertension and increased circulating levels of AII in both double transgenic and now single transgenic animals suggests that the regulatory elements responsible for responding to baroreceptor inputs and AII lie further upstream of the 900 bp 5' flanking region employed in our construct.
