Mechanotransduction signaling in podocytes from fluid flow shear stress

Tarak Srivastava, Hongying Dai, Daniel P. Heruth, Uri S. Alon, Robert E. Garola, Jianping Zhou, R. Scott Duncan, Ashraf El-Meanawy, Ellen T. McCarthy, Ram Sharma, Mark L. Johnson, Virginia J. Savin, Mukut Sharma

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 podocytes. Our previous work suggests that the cyclooxygenase-2 (COX-2)- PGE2-PGE2 receptor 2 (EP2) axis plays an important role in mechanoperception of FFSS in podocytes. To address mechanotransduction of the perceived stimulus through EP2, cultured podocytes were exposed to FFSS (2 dyn/cm 2 ) for 2 h. Total RNA from cells at the end of FFSS treatment, 2-h post-FFSS, and 24-h post-FFSS was used for whole exon array analysis. 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 MAPK/ERK 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. The current regimen for treating hyperfiltration-mediated injury largely depends on targeting the renin-angiotensin-aldosterone system. The present study identifies specific transduction mechanisms and provides novel information on the direct effect of FFSS on podocytes. These results suggest that targeting EP2- mediated signaling pathways holds therapeutic significance for delaying progression of chronic kidney disease secondary to hyperfiltration.

Original languageEnglish (US)
Pages (from-to)F22-F34
JournalAmerican Journal of Physiology - Renal Physiology
Volume314
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • Exon array analysis
  • Fluid flow shear stress
  • Hyperfiltration
  • Mechanotransduction
  • Podocytes

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Srivastava, T., Dai, H., Heruth, D. P., Alon, U. S., Garola, R. E., Zhou, J., Duncan, R. S., El-Meanawy, A., McCarthy, E. T., Sharma, R., Johnson, M. L., Savin, V. J., & Sharma, M. (2018). Mechanotransduction signaling in podocytes from fluid flow shear stress. American Journal of Physiology - Renal Physiology, 314(1), F22-F34. https://doi.org/10.1152/ajprenal.00325.2017