Hamzeh MT, Sridhara R, Alexander LD. Cyclic stretch-induced TGF-1 and fibronectin expression is mediated by 1-integrin through c-Src-and STAT3-dependent pathways in renal epithelial cells.
Extracellular matrix accumulation contributes to the progression of chronic renal disease. Recent in vivo data indicate that unilateral ureteral obstruction (UUO), a model for chronic obstructive nephropathy, induces profibrotic renal tubular cell injury via STAT3 activation. A characterization of obstructive nephropathy and UUO is an increase in intrarenal pressure resulting in tubular mechanical stretch. However, in the kidney, the influence of mechanical strain on renal tubular epithelial (RTE) cells remains unclear. It is possible that tubular mechanical strain may attribute to increased STAT3 activation leading to accumulation of the extracellular matrix protein, fibronectin, in RTE cells. Human proximal tubular HK‐2 cells were either or not subjected to cyclic mechanical stretch on a uniform biaxial strain device. Fibronectin expression increased significantly in response to cyclic stretch, which was attenuated by inhibition of cPLA2, but not sPLA2 or iPLA2. In addition, treatment of cells with arachidonic acid resulted in an increased expression of fibronectin. Cyclic stretch also stimulated phosphorylation of STAT3 and Akt, and inhibition of STAT3, Akt, or its upstream activator phosphatidyl inositol 3‐kinase (PI3‐K), attenuated stretch‐induced fibronectin accumulation. Expression of dominant negative Akt or transfection of small interfering RNA targeting STAT3 significantly blocked stretch‐induced increase in fibronectin, indicating a role for these kinases in fibronectin accumulation. Taken together, these results provide the first evidence for a role of cPLA2, STAT3, and Akt in stretch‐induced fibronectin expression in RTE cells.
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