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Inhibition by Phorbol Ester of Cellular Adenosine 3',5'-Monophosphate Production and Cellular Free Calcium Mobilization in Response to Arginine Vasopressin in Rat Renal Papillary Collecting Tubule Cells in Culture^*

Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School Tochigi 329–04 Japan

Abstract

We determined whether tumor-promoting factor phorbol ester modulates cellular cAMP production and the cellular free calcium concentration ([Ca2+]i) in response to arginine vasopressin (AVP) in rat renal papillary collecting tubule cells in culture. In the presence of 5 x 10^-4 M 3-isobutyl-l-methylxanthine, AVP increased cellular cAMP production in a dosedependent manner. A 1-h exposure to 3 x 10^-7-3 x 10^-6 M phorbol-12-myristate-13-acetate (PMA) significantly attenuated the cAMP response to AVP (1 x 10^-9 M AVP; 474.9 ± 24.8 vs. 368.1 ± 22.8 fmol/µg protein; P < 0.01 ). The dose-response relation with AVP thus shifted to the right. Such an inhibition was totally reversed in the presence of 2 x 10^-6 M l-(5-isoquinolinesulfonyl)- 2-methylpiperazine dihydrochloride (H-7), an inhibitor of protein kinase-C. Also, 1 x 10^-7 M AVP produced an increase in [Ca²⁺]_i from 99.4 ± 3.3 to 200.0 ± 8.6 nM. When cells were preexposed to 1 x 10^-6 M PMA, an increase in [Ca²⁺]_i in response to 1 x 10^-7 M AVP was significantly diminished (75.5 ± 4.6 to 101.4 ± 4.3 nM). The inhibition by PMA of AVPinduced increment in [Ca²⁺]_i was significantly attenuated in the presence of 2 x 10^-6 M H-7 compared to that in its absence. Prolonged exposure to PMA did not alter the AVP-induced increases in cAMP production and [Ca²⁺]_i. These results indicate that phorbol ester inhibits the cellular action of AVP mediated through the activation of protein kinase-C and suggest that there is an interaction between cAMP and phosphatidylinositol systems in modulating the AVP action in renal papillary collecting tubule cells. (Endocrinology 128: 786–791, 1991)

Footnotes

^* This work was supported by a grant from the Ministry of Education, Science, and Culture of Japan.

Received June 22, 1990.