Aberrant ETB receptor regulation of AT1 receptors in immortalized renal proximal tubule cells of spontaneously hypertensive rats

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The renin-angiotensin and endothelin systems interact to regulate blood pressure, in part, by affecting sodium transport in the kidney. Because angiotensin II type 1 (AT(1)) receptor activation increases ETB receptor expression in renal proximal tubule cells from Wistar-Kyoto (WKY) rat, we hypothesize that ETB receptor activation may also regulate AT(1) receptor expression. Furthermore, ETB receptor regulation of the AT(1) receptor may be different in the WKY and spontaneously hypertensive rat (SHR). AT(1) and ETB receptors were studied in immortalized renal proximal tubule cells from WKY and SHRs, using immunoblotting, confocal microscopic colocalization, and immunoprecipitation. In WKY renal proximal tubule cells, an ETB receptor agonist, BQ3020, decreased AT(1) receptor protein in a time- and concentration-dependent manner [median effective concentration (EC(50)) = 3.2 x 10(-10) mol/L, t(1/2)= 15 hours]. The inhibitory effect of BQ3020 (10(-8) mol/L/24 hours) on AT(1) receptor protein was blocked by an ETB receptor antagonist (BQ788). However, BQ3020 (10(-8) mol/L/24 hours) increased ETB receptor protein in WKY renal proximal tubule cells. In contrast, in SHR renal proximal tubule cells, BQ3020 (10(-8) mol/L/24 hours) no longer affected AT(1) or ETB receptor protein. AT(1)/ETB receptors colocalized and coimmunoprecipitated in WKY and SHRs. BQ3020 (10(-8) mol/L/15 minutes) treatment had no effect on AT(1)/ETB coimmunoprecipitation in WKY but decreased it in SHRs. BQ3020 (10(-8) mol/L/15 minutes) treatment increased AT(1) receptor phosphorylation in WKY, but decreased it in SHRs. ETB receptors regulate AT(1) receptors by direct physical receptor interaction and receptor expression. An impaired ETB receptor regulation of the AT(1) receptor may participate in the pathogenesis of high blood pressure in the SHR.