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Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes.

The ultrafiltrate flow over the major processes and cell body generates fluid flow shear stress (FFSS) on podocytes. Hyperfiltration-associated increase in FFSS can lead to podocyte injury and detachment. Previously, we showed that FFSS-induced upregulation of the COX2-PGE2-EP2 axis in podocytes activates the Akt-GSK3β-β-catenin and MAPK/ERK signaling in response to FFSS. Integrative MultiOmics Pathway Resolution (IMPRes) is a new bioinformatic tool that enables simultaneous time-series analysis of more than two groups to identify pathways and molecular connections. In this present study, we used previously characterized Ptgs2, Ptger2, and Ctnnb1 as "seed genes" from an array dataset of four groups analyzed over a time course. The three seed genes shared seven pathways and 50 genes of the total 14 pathways and 89 genes identified by IMPRes. A composite of signaling pathways highlighted the temporal molecular connections during mechanotransduction signaling in FFSS-treated podocytes. We investigated the "Proteoglycans in cancer" and "Galactose metabolism" pathways predicted by IMPRes. A custom-designed PCR array validated 60.7% of the genes predicted by IMPRes analysis, including ones for the abovenamed pathways. Further validation using Western Blot analysis showed increased expression of phosho-Erbb2, phospho-mTOR, CD44, and Hk2; decreased total Erbb2, Galm, and B4galt1; and unchanged total mTOR and AKT3. These findings corroborate our previously reported results. This study demonstrates the potential of the IMPRes method to identify novel pathways. Identifying the "Proteoglycans in cancer" and "Galactose metabolism" pathways generated a lead to study the significance of FFSS-induced glycocalyx remodeling and possible detachment of podocytes from the glomerular matrix.