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Shear Stress Dependent Regulation of Apical Endocytosis in Renal Proximal Tubule Epithelia
Author(s) -
Raghavan Venkatesan,
Rbaibi Youssef,
Carattino Francisco,
Carattino Marcelo,
Weisz Ora
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.809.4
Subject(s) - endocytic cycle , endocytosis , microbiology and biotechnology , internalization , dynamin , clathrin , chemistry , receptor mediated endocytosis , apical membrane , reabsorption , bulk endocytosis , biology , receptor , kidney , biochemistry , endocrinology , membrane
The kidney has an extraordinary ability to maintain stable fractional solute and fluid reabsorption over a wide range of glomerular filtration rates (GFRs). Internalization of filtered low molecular weight proteins, vitamins, hormones, and other small molecules is mediated by the proximal tubule (PT) multiligand receptors megalin and cubilin. Changes in GFR and the accompanying fluid shear stress (FSS) modulate acute changes in PT ion transport. Therefore, we hypothesized that changes in FSS would also modulate protein uptake. We recently discovered that FSS also modulates apical endocytosis in PT cells via a mechanosensitive pathway regulated by primary cilia . FSS caused a rapid and transient increase in intracellular calcium in cells that preceded the endocytic response. Neither the FSS‐stimulated increase in intracellular calcium or apical endocytosis was observed in deciliated cells. Addition of ATP to the medium rescued both responses, suggesting the involvement of purinergic receptors in the signaling cascade. Both basal and FSS‐stimulated endocytosis were inhibited by inhibitors of clathrin and dynamin. Additionally, treatment of PT cells with small molecule inhibitors of Cdc42 or siRNA mediated knockdown of Cdc42 ablated the FSS‐stimulated increase in endocytosis. Similarly knockdown of N‐WASP which participates in nucleation of branched actin filaments prevented the FSS stimulated endocytic response. Our data suggest that exposure of PT cells to FSS enhances apical clathrin‐mediated endocytosis via an actin‐dependent pathway that is modulated by activation of Cdc42, and N‐WASP. Our work defines a novel mechanism that underlies effective protein retrieval by the kidney.