Ion Channels – Membrane Transport – Integrative Physiology

Kidney International (2005) 68, 623–631; doi:10.1111/j.1523-1755.2005.00440.x

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

CHUNYU ZENG, ZHENG WANG, LAUREANO D ASICO, ULRICH HOPFER, GILBERT M EISNER, ROBIN A FELDER and PEDRO A JOSE

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China; Department of Pediatrics, Georgetown University Medical Center, Washington, DC; Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC; Department of Internal Medicine, Georgetown University Medical Center, Washington, DC; Department of Physiology, Case Western Reserve School of Medicine, Cleveland, Ohio; Department of Pathology, University of Virginia Health Science Center, Charlottesville, Virginia

Correspondence: Dr Chunyu Zeng, Department of Pediatrics, PHC-2, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, DC 20007. E-mail: cyzeng1@hotmail.com

Received 13 December 2004; Revised 3 February 2005; Accepted 8 March 2005.

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Abstract

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

Background

 

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 (AT1) 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 AT1 receptor expression. Furthermore, ETB receptor regulation of the AT1 receptor may be different in the WKY and spontaneously hypertensive rat (SHR).

Method

 

AT1 and ETB receptors were studied in immortalized renal proximal tubule cells from WKY and SHRs, using immunoblotting, confocal microscopic colocalization, and immunoprecipitation.

Results

 

In WKY renal proximal tubule cells, an ETB receptor agonist, BQ3020, decreased AT1 receptor protein in a time- and concentration-dependent manner [median effective concentration (EC50) = 3.2 times 10-10 mol/L, t1/2 = 15 hours]. The inhibitory effect of BQ3020 (10-8 mol/L/24 hours) on AT1 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 AT1 or ETB receptor protein. AT1/ETB receptors colocalized and coimmunoprecipitated in WKY and SHRs. BQ3020 (10-8 mol/L/15 minutes) treatment had no effect on AT1/ETB coimmunoprecipitation in WKY but decreased it in SHRs. BQ3020 (10-8 mol/L/15 minutes) treatment increased AT1 receptor phosphorylation in WKY, but decreased it in SHRs.

Conclusion

 

ETB receptors regulate AT1 receptors by direct physical receptor interaction and receptor expression. An impaired ETB receptor regulation of the AT1 receptor may participate in the pathogenesis of high blood pressure in the SHR.

Keywords:

essential hypertension, angiotensin II receptors, endothelin, kidney, phosphorylation

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