Recently we and others have found that hyperfiltration-associated increase in biomechanical forces, namely tensile stress and fluid flow shear stress (FFSS) can directly and distinctly alter podocyte structure and function. The ultrafiltrate flow over the major processes and cell body generates FFSS to podocyte. Our previous work suggests that COX2-PGE2-EP2 axis plays an important role in mechanoperception of FFSS in podocyte (Srivastava et al. Am J Physiol Renal Physiol 307: F1323-F1333, 2014). To address mechanotransduction of the perceived mechanical stimulus through EP2 receptor, cultured podocytes were exposed to FFSS (2 dynes/cm2) for 2hrs. Total RNA from cells at the end of treatment, 2h post-FFSS and 24h post-FFSS was used for whole exon array analysis. The differentially regulated genes (p<0.01) were analyzed using bioinformatics tools Enrichr and Ingenuity Pathway Analysis to predict pathways/ molecules. Candidate pathways were validated using Western blot analysis, and then further confirmed to be resulting from a direct effect of PGE2 on podocytes. Results show that FFSS-induced mechanotransduction as well as exogenous PGE2 activate the Akt-GSK3β-β-catenin (Ser552) and ERK/MAPK but not the cAMP-PKA signal transduction cascades. These pathways are reportedly associated with FFSS-induced and EP2-mediated signaling in other epithelial cells as well. Current regimen for treating hyperfiltration-mediated injury largely depends on targeting the Renin-Angiotensin-Aldosterone System. Present study identifies specific transduction mechanisms and provides novel information on the direct effect of FFSS on podocytes. These results suggest that targeting EP2 receptor-mediated signaling pathways holds therapeutic significance for delaying progression chronic kidney disease secondary to hyperfiltration.