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Rho-family small GTPases are involved in forskolin-induced cell-cell contact formation of renal glomerular podocytes in vitro
Authors:Gao Shuang-Yan  Li Chun-Yu  Shimokawa Tetsuya  Terashita Takehiro  Matsuda Seiji  Yaoita Eishin  Kobayashi Naoto
Institution:(1) Department of Anatomy and Embryology, School of Medicine, Ehime University, To-on City Ehime, 791-0295, Japan;(2) Department of Infectious Diseases, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, 110001, China;(3) Department of Structural Pathology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;(4) Present address: Medical Education Center, Ehime University School of Medicine, Shitsukawa, To-on City Ehime, 791-0295, Japan
Abstract:Intercellular adhesions between renal glomerular epithelial cells (also called podocytes) are necessary for the proper function of the glomerular filtration barrier. Although our knowledge of the molecular composition of podocyte cell-cell contact sites has greatly progressed, the underlying molecular mechanism regulating the formation of these cell-cell contacts remains largely unknown. We have used forskolin, an activator of adenylyl cyclase that elevates the level of intracellular cAMP, to investigate the effect of cAMP and three Rho-family small GTPases (RhoA, Cdc42, and Rac1) on the regulation of cell-cell contact formation in a murine podocyte cell line. Transmission electron microscopy and the immunostaining of cell adhesion molecules and actin-associated proteins have revealed a structural change at the site of cell-cell contact following forskolin treatment. The activity of the Rho-family small GTPases before and after forskolin treatment has been evaluated with a glutathione-S-transferase pull-down assay. Forskolin reinforces the integrity of cell-cell contacts, resulting in the closure of an intercellular adhesion zipper, accompanied by a redistribution of cell adhesion molecules and actin-associated proteins in a continuous linear pattern at cell-cell contacts. The Rho-family small GTPases Rac1 and Cdc42 are activated during closure of the adhesion zipper, whereas RhoA is suppressed. Thus, cAMP promotes the assembly of cell-cell contacts between podocytes via a mechanism that probably involves Rho-family small GTPases. This study was supported in part by a grant-in-aid for scientific research from the Japanese Ministry for Education, Culture, Sports, Science, and Technology (to N. K., no. 14570015). S-Y.G. is a recipient of a grant awarded by the Japanese government to graduate students from foreign countries.
Keywords:Renal glomerulus  Podocyte  Cell-cell contact  cAMP  Rho-family small GTPases  Mouse
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