Angiotensin-(1-7) reduces renal angiotensin II receptors through a cyclooxygenase-dependent mechanism

In the kidney, angiotensin-(1-7) [Ang-(1-7)] exhibits diuretic and natriuretic properties associated with an increase in prostaglandin production. The prohypertensive effects of Ang II are attenuated in rats infused with Ang-(1-7), consistent with recent work showing that Ang-(1-7) downregulates AT(1) receptors in Chinese hamster ovary-AT(1A) or vascular smooth muscle cells. To determine whether exposure to Ang-(1-7) reduces AT(1) receptors in the kidney through an increase in prostaglandin production, kidney slices from Sprague-Dawley rats were incubated with 10 nM-1 muM Ang-(1-7) in the presence or absence of 5 muM meclofenamate, a cyclooxygenase inhibitor. Following these treatments, the kidney slices were retrieved, frozen, and sectioned for determination of [I-125]-Ang II binding using in vitro receptor autoradiography. Greater than 90% of the specific binding was competed for by losartan, indicating that the majority of binding was to the AT(1) receptor. Incubation of kidney slices with 1 muM Ang-(1-7) caused a 20% reduction in [I-125]-Ang II binding (n = 8) in the cortical tubulointerstitium, which was prevented when Ang-(1-7)-treated slices were incubated in the presence of 5 muM meclofenamate (1 +/- 2% increase, n = 8; p < 0.05). Incubation with 5 muM meclofenamate alone had no effect on [1251]-Ang II binding (-3 +/- 3%). The decrease in [1251] -Ang II binding with Ang-(1-7) was also blocked by the Ang-(1-7) antagonist [D-Ala(7)]-Ang-(1-7). Treatment with 1 muM [D-Ala(7)]- Ang-(1-7) alone had no effect on [I-125]-Ang II binding (-3 +/- 6% of control). Pretreatment with 1 muM Ang II caused a similar reduction in [I-125]-Ang II binding in the cortical tubulointerstitium. Neither Ang-(1-7) nor Ang II had any effect on [I-125]-Ang II binding in the glomeruli and the area of the vasa recta of the kidney. These original findings suggest that prior exposure to Ang-(1-7) or Ang II causes a modest decrease in the number of AT, receptors in the cortical tubulointerstitial area of the kidney. The reduction in Ang II binding by Ang-(1-7) was blocked by meclofenamate and [D-Ala(7)]-Ang-(1-7), suggesting that cyclooxygenase products released through activation of a novel receptor participate in this effect.