Overexpression of HIF-1α transgene in the renal medulla attenuated salt sensitive hypertension in Dahl S rats

Abstract

Hypoxia inducible factor (HIF)-1α-mediated gene activation in the renal medulla in response to high salt intake plays an important role in the control of salt sensitivity of blood pressure. High salt-induced activation of HIF-1α in the renal medulla is blunted in Dahl S rats. The present study determined whether the impairment of the renal medullary HIF-1α pathway was responsible for salt sensitive hypertension in Dahl S rats. Renal medullary HIF-1α levels were induced by either transfection of HIF-1α expression plasmid or chronic infusion of CoCl₂ into the renal medulla, which was accompanied by increased expressions of anti-hypertensive genes, cyclooxygenase-2 and heme oxygenase-1. Overexpression of HIF-1α transgenes in the renal medulla enhanced the pressure natriuresis, promoted the sodium excretion and reduced sodium retention after salt overload. As a result, hypertension induced by 2-week high salt was significantly attenuated in rats treated with HIF-1α plasmid or CoCl₂. These results suggest that an abnormal HIF-1α in the renal medulla may represent a novel mechanism mediating salt-sensitive hypertension in Dahl S rats and that induction of HIF-1α levels in the renal medulla could be a therapeutic approach for the treatment of salt-sensitive hypertension.

Figure 1. Effects of renal medullary transfection of HIF-1α transgene or CoCl₂ infusion on HIF-1α levels in the renal medulla

A: Representative ECL gel documents of Western blot analyses depicting the protein levels of HIF-1α. B: Summarized intensities of the HIF-1α blots (ratio to β-actin). * P < 0.05 vs. control (n=6). LS = low salt + control vectors, HS = high salt + control vectors, HIF-1α = HIF-1α expression vectors, CoCl₂ = CoCl₂ infusion..

Figure 2. Effect of HIF-1α transgene overexpression or CoCl₂ infusion on the mRNA levels of HIF-1α target genes HO-1 and COX2 in the renal medulla

* P < 0.05 vs. others including LS group (n=6).

Figure 3. Effects of renal medullary transfection of HIF-1α transgene on pressure natriuresis

A: urine flow rates (U·V) in response to the elevations of renal perfusion pressure (RPP). B: urinary sodium excretion rates (U_Na·V) in response to the elevations of RPP. * P < 0.05 vs. control (n=6).

Figure 4. Effects of renal medullary transfection of HIF-1α transgene on U·V (A) and U_Na·V (B) in response to acute Na+ loading

* P < 0.05 vs. control (n=6). S=sodium loading; P=post sodium loading.

Figure 5. Effects of renal medullary transfection of HIF-1α transgene on salt balances

A: daily sodium balance. B: cumulative sodium balance. * P < 0.05 vs. HIF-1α (n=6).

Figure 6. Effects of renal medullary transfection of HIF-1α transgene or CoCl₂ infusion

on mean arterial pressure (MAP). * P < 0.05 vs. others. (n=6).