Cell-cell contacts via N-cadherin induce a regulatory renin secretory phenotype in As4.1 cells
Jai Won Chang1,2, Soohyun Kim1, Eun Young Lee3, Chae Hun Leem1, Suhn Hee Kim4, and Chun Sik Park1,*
1Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, 2Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, 3Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul 06591, 4Department of Physiology, Jeonbuk National University Medical School, Jeonju 54907, Korea
Author contributions: S.K. performed experiments. J.W.C., E.Y.L., and S.H.K. prepared graphics and performed statistical analyses. C.H.L. conducted imaging of renin exocytosis. J.W.C. wrote the first draft. C.S.P. conceived and supervised the project and finalized the manuscript. All authors have read and approved the final version of the manuscript.
Received: June 13, 2022; Revised: September 5, 2022; Accepted: September 19, 2022
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The lack of a clonal renin-secreting cell line has greatly hindered the investigation of the regulatory mechanisms of renin secretion at the cellular, biochemical, and molecular levels. In the present study, we investigated whether it was possible to induce phenotypic switching of the renin-expressing clonal cell line As4.1 from constitutive inactive renin secretion to regulated active renin secretion. When grown to postconfluence for at least two days in media containing fetal bovine serum or insulin-like growth factor-1, the formation of cell-cell contacts via N-cadherin triggered downstream cellular signaling cascades and activated smooth muscle-specific genes, culminating in phenotypic switching to a regulated active renin secretion phenotype, including responding to the key stimuli of active renin secretion. With the use of phenotype-switched As4.1 cells, we provide the first evidence that active renin secretion via exocytosis is regulated by phosphorylation/dephosphorylation of the 20 kDa myosin light chain. The molecular mechanism of phenotypic switching in As4.1 cells described here could serve as a working model for full phenotypic modulation of other secretory cell lines with incomplete phenotypes.