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Tyrosine Kinase and Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase Differentially Regulate Intracellular Calcium Concentration Responses to Angiotensin II/III and Bradykinin in Rat Cortical Thick Ascending Limb

Institut National de la Santé et de la Recherche Médicale Unité 691 (A.H.-C., X.I., C.L.-C.) and Unité 36 (P.C.), Collège de France, 75231 Paris, France; and Institut National de la Santé et de la Recherche Médicale Unité 367 (J.M.), 75005 Paris, France

Address all correspondence and requests for reprints to: Catherine Llorens-Cortes, Institut National de la Santé et de la Recherche Médicale Unité 691, Collège de France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France. E-mail: c.llorens-cortes{at}college-de-france.fr.

The cortical thick ascending limb (CTAL) coexpresses angiotensin (Ang) II/Ang III receptor type 1A (AT_1A-R) and bradykinin (BK) receptor type 2 (B₂-R). In several cell types, these two receptors share the same signaling pathways, although their physiological functions are often opposite. In CTAL, little is known about the intracellular transduction events leading to the final physiological response induced by these two peptides. We investigated and compared in this segment the action of Ang II/III and BK on intracellular calcium concentration ([Ca²⁺]_i) response and metabolic CO₂ production, an index of Na⁺ transport, by using inhibitors of protein kinase C (bisindolylmaleimide), Src tyrosine kinase (herbimycin A and PP2), and MAPK/ERK (PD98059 and UO126). Ang II/III and BK (10^–7 mol/liter) released Ca²⁺ from the same intracellular pools but activated different Ca²⁺ entry pathways. Ang II/III- or BK-induced [Ca²⁺]_i increases were similarly potentiated by bisindolylmaleimide. Herbimycin A and PP2 decreased similarly the [Ca²⁺]_i responses induced by Ang II/III and BK. In contrast, PD98059 and UO126 affected the effects of BK to a larger extent than those of Ang II/III. Especially, the Ca²⁺ influx induced by BK was more strongly inhibited than that induced by Ang II/III in the presence of both compounds. The Na⁺ transport was inhibited by BK and stimulated by Ang II/III. The inhibitory action of BK on Na⁺ transport was blocked by UO126, whereas the stimulatory response of Ang II/III was potentiated by UO126 but blocked by bisindolylmaleimide. These data suggest that the inhibitory effect of BK on Na⁺ transport seems to be directly mediated by an increase in Ca²⁺ influx dependent on MAPK/ERK pathway activation. In contrast, the stimulatory effect of Ang II/III on Na⁺ transport is more complex and involves PKC and MAPK/ERK pathways.