Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes
| Autor: | Ram Sharma, Robert E. Garola, Uri Alon, Yuexu Jiang, Varun C. Boinpelly, Jianping Zhou, Daniel P. Heruth, Virginia J. Savin, Ashraf El-Meanawy, Mohamed H. Rezaiekhaligh, Vincent S. Staggs, Mukut Sharma, Jan Novak, Trupti Joshi, Tarak Srivastava, Ellen T. McCarthy |
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| Rok vydání: | 2020 |
| Předmět: |
Transcriptional Activation
0301 basic medicine MAPK/ERK pathway Physiology Kidney Glomerulus Mechanotransduction Cellular Podocyte 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine Mechanotransduction education PI3K/AKT/mTOR pathway education.field_of_study biology Podocytes Chemistry TOR Serine-Threonine Kinases Receptors Prostaglandin E EP2 Subtype Up-Regulation Cell biology 030104 developmental biology medicine.anatomical_structure Proteoglycan Cyclooxygenase 2 030220 oncology & carcinogenesis biology.protein Proteoglycans Stress Mechanical Galactose mutarotase Signal transduction Research Article |
| Zdroj: | Am J Physiol Renal Physiol |
| ISSN: | 1522-1466 1931-857X |
| DOI: | 10.1152/ajprenal.00183.2020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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