Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats

The angiotensin II type 2 (AT(2)) receptor is present in rat kidney; howeve r, its function is Dot well understood. The purpose of this study was to ev aluate the role of the AT(2) receptor In blood pressure (BP) regulation. Th e effects of selective inhibition of the renal AT(2) receptor with phosphor othioated antisense oligodeoxynucleotide (AS-ODN) were examined in consciou s uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN ]) were infused directly into the renal interstitial space by using an osmo tic pump at 1 muL/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral, kidney of normal r ats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, c aused a significant (P<0.01) increase in BP 1 to 5 days after the initiatio n of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109<plus/minus>4 to 130 +/-4 mm Hg (n=8, P<0.01), whereas S-ODN-tre ated (n=8) and vehicle-treated (n=8) rats did not show any significant chan ge in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rat s exhibited a greater presser response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (P<0.01). Renal interstitia l fluid cGMP decreased from 11.9 +/-0.8 to 3.6 +/-0.5 pmol/mL (P<0.001), an d bradykinin decreased from 0.05<plus/minus>0.05 to 0.18 +/-0.03 ng/mL (P<0 .001) in response to AS-ODN, but they were not significantly changed in res ponse to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT(2) recept or expression, Western Blot analysis was performed on treated kidneys. Kidn eys treated with AS-ODN had <approximate to>40% less expression of AT(2) re ceptor than did kidneys treated with S-ODN or vehicle (P<0.05). These resul ts suggest that AS-ODN directed selectively against the renal AT(2) recepto r decreased receptor expression and caused an increase in BP. We conclude t hat the renal AT(2) receptor plays an important role in the regulation of B P via a bradykinin/cGMP vasodilator signaling cascade.