Renin, endothelial NO synthase and endothelin gene expression in the 2kidney-1clip Goldblatt model of long-term renovascular hypertension

Abstract

Objective: Numerous reports have shown the influence of renin, nitric oxide (NO) and the endothelin (ET) systems for regulation of blood pressure and renal function. Furthermore, interactions between these peptides have been reported. Aim of our study was to investigate the relative contribution of these compounds in long-term renovascular hypertension / renal ischemia.

Methods: Hypertension / left-sided renal ischemia was induced using the 2K1C-Goldblatt rat model. Renal renin, ET-1, ET-3 and endothelial NO synthase (eNOS) gene expression was measured by means of RNAse protection assay at different timepoints up to 10 weeks after induction of renal artery stenosis.

Results: Plasma renin activity and renal renin gene expression in the left kidney were increased in the clipped animals while eNOS expression was unchanged. Furthermore, an increase in ET-1 expression and a decrease of ET-3 expression was detected in early stenosis.

Conclusions: While renin is obviously involved in regulation of blood pressure and renal function in unilateral renal artery stenosis, ET-1, ET-3 and endothelium derived NO do not appear to play an important role in renal adaptation processes in long-term renal artery stenosis, although ET-1 and ET-3 might be involved in short-term adaptation processes.

Figure 1

Kidney weight in the 2K1C group and control group at different timepoints after surgery. Kidney weight of the unclipped kidneys increased by time. It was significantly higher compared to the clipped kidneys starting at day 7. The contralateral (unclipped) kidney had a higher weight compared to the control group starting at day 28. The weight of the clipped kidneys was significantly lower than control starting at day 3 and did not change significantly over time (significant vs. control *; significant vs. contralateral side #, p < 0.05).

Figure 2

Systolic blood pressure after clipping and sham-operation. Systolic blood pressure significantly increased in the 2K1C-group to 162.5 ± 8 mmHg on day 1, 179 ± 11 mmHg on day 2 and 189 ± 7 mmHg on day 20 after clipping, thereafter levelling off at slightly lower levels (155 ± 7 mmHg at day 40 and 149 ± 3 mmHg at day 63). The control group presented significantly lower systolic blood pressure values at every postoperative timepoint (significant vs. control *, p < 0.05).

Figure 3

Plasma renin activity in the clipped and unclipped group. Plasma renin activity in the 2K1C-group was six times higher than in the control group at day 3. Plasma renin activity then decreased to about 3.5 fold on days 7, 12 and 28 and to about 2 fold of control group on day 70 (significant vs. control *, p < 0.05).

Figure 4

Gene expression of renin in the clipped and unclipped kidneys (K) at different time-points after surgery. Renal renin gene expression was higher at all timepoints in the clipped kidney compared with the unclipped kidney and at day 3 to 28 compared to control, whereas the contralateral kidney displayed renin gene suppression to ~50% of control at day 3 to 12 (significant vs. control *; significant vs. contralateral side #, p < 0.05).

Figure 5

Gene expression of ET-1 in the clipped and unclipped kidneys (K) at different time-points after surgery. ET-1 gene expression tended to increase with time in all groups and was significantly higher in the clipped kidney on day 7 compared with the contralateral kidney (significant vs. contralateral side *, 90.4 ± 6.7 vs. 71.2 ± 5.5, p < 0.05).

Figure 6

Gene expression of ET-3 in the clipped and unclipped kidneys (K) at different time-points after surgery. ET-3 gene expression was significantly lower in the clipped kidneys compared with the contralateral kidney at day 3 (significant vs. contralateral side *, 55.7 ± 7.7 vs. 70.6 ± 7.3, p < 0.05).