Cyclic stretch‐induced proliferation in rabbit proximal tubular cells involves cPLA2, ERK, and c‐Src

Abstract

Increased intrarenal pressure, in unilateral uretal obstruction (UUO), is considered a major event leading to persistent tubular cell proliferation. The mechanical signal produced by UUO is assumed to be tubular stretching, but the molecular mechanisms involved in this process are poorly understood. In the present study we investigated whether a "physiological" level of stretch (5%) or a more injurious magnitude of stretch (15%) can induce proliferation in kidney epithelial cells. To produce strain or stretch, primary cultures of rabbit proximal tubular cells were grown in tissue culture wells having collagen‐coated Silastic deformable membrane bottoms and exposed to 5% or 15% stretch for 6 h or 24 h. We found that cyclic stretch significantly induced the proliferation of rabbit proximal tubular cells at both 5% and 15% strain for 24 h. Inhibition of PLA2 by AACOCF3 or with the antisense oligonucleotide treatment designed to silence cPLA2 expression, EK 1/2 by PD98059 and c‐Src by a selective inhibitor for the Src kinase family, PP2 or with a dominant‐negative (DN) mutants of c‐Src, blocked the cyclic stretch‐induced proliferation. Overall, this study demonstrates, for the first time, that cyclic mechanical stretch induces the proliferation of rabbit proximal tubular cells and suppresses their mitogenic affect through the activation of cPLA2, ERK and c‐Src.