Laboratory Investigation

Kidney International (1994) 46, 666–674; doi:10.1038/ki.1994.319

Mechanism of insulin-stimulated electrogenic sodium transport

Jose Rodriguez-Commes1, Carlos Isales1, Leena Kalghati1, Jose Gasalla-Herraiz1 and John P Hayslett1

1Department of Medicine, Sections of Nephrology and Endocrinology, Yale School of Medicine, New Haven, Connecticut, USA

Correspondence: John P Hayslett MD, Yale School of Medicine, 333 Cedar Street, P. O. Box 8029, New Haven, Connecticut 06520-208029, USA

Received 15 November 1993; Revised 4 April 1994; Accepted 7 April 1994.

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Abstract

Mechanisms of insulin-stimulated electrogenic sodium transport. Studies were performed to determine the signal transduction mechanism involved in the onset of insulin stimulated electrogenic sodium transport (Ieq) in cultured A6 cells. Insulin stimulated Ieq at a threshold concentration of one nM and a half-maximum concentration of approximately 3 nM. The onset of action occurred within 10 seconds and the increase in Ieq was augmented by pretreatment with aldosterone, similar to the action of vasopressin. Insulin stimulated an increase in Cai2+ in a dose-dependent manner that involved release from intracellular stores. Hormone stimulated Ieq was dependent on increases in Cai2+ because pretreatment with 5, 5' dimethyl BAPTA/AM blocked the increase in sodium transport. further studies with dihydroxyclorpromazine, trifluoperazine and genistein, inhibitors of PKC, Cai2+ dependent, calmodulin dependent kinases and tyrosine kinase, respectively, suggested that the action of insulin was dependent on activation of these kinases. In contrast, insulin stimulated Ieq was independent of changes in cAMP, because insulin did not increase the accumulation of cAMP, and inhibition of adenylate cyclase with 2', 5' dideoxyadenosine did not affect transport. These results suggest that insulin, as previously shown for aldosterone, activates apical membrane amiloride sensitive sodium channels by a calcium-dependent second messenger system.

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