Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes. Am J Physiol Renal Physiol 2020 Aug 01;319(2):F312-F322
Date
07/07/2020Pubmed ID
32628542Pubmed Central ID
PMC7473905DOI
10.1152/ajprenal.00183.2020Scopus ID
2-s2.0-85089301199 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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 cyclooxygenase 2 (COX2)-PGE2-prostaglandin E receptor 2 (EP2) axis in podocytes activates Akt-glycogen synthase kinase-3β-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 the present study, we used previously characterized COX2 [prostaglandin-endoperoxide synthase 2 (Ptgs2)], EP2 (Ptger2), and β1-catenin (Ctnnb1) as "seed genes" from an array data set of four groups analyzed over a time course. The 3 seed genes shared 7 pathways and 50 genes of 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 genes for the above-named pathways. Further validation using Western blot analysis showed increased expression of phosho-Erbb2, phospho-mammalian target of rapamycin (mTOR), CD44, and hexokinase II (Hk2); decreased total Erbb2, galactose mutarotase (Galm), and β-1,4-galactosyltransferase 1 (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 has generated a lead to study the significance of FFSS-induced glycocalyx remodeling and possible detachment of podocytes from the glomerular matrix.
Author List
Srivastava T, Joshi T, Jiang Y, Heruth DP, Rezaiekhaligh MH, Novak J, Staggs VS, Alon US, Garola RE, El-Meanawy A, McCarthy ET, Zhou J, Boinpelly VC, Sharma R, Savin VJ, Sharma MAuthor
Ashraf El-Meanawy MD, PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cyclooxygenase 2Kidney Glomerulus
Mechanotransduction, Cellular
Podocytes
Proteoglycans
Receptors, Prostaglandin E, EP2 Subtype
Stress, Mechanical
TOR Serine-Threonine Kinases
Transcriptional Activation
Up-Regulation