Mechanotransduction signaling in podocytes from fluid flow shear stress. Am J Physiol Renal Physiol 2018 Jan 01;314(1):F22-F34
Date
09/08/2017Pubmed ID
28877882Pubmed Central ID
PMC5866353DOI
10.1152/ajprenal.00325.2017Scopus ID
2-s2.0-85043506758 (requires institutional sign-in at Scopus site) 32 CitationsAbstract
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/cm2) 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.
Author List
Srivastava T, Dai H, Heruth DP, Alon US, Garola RE, Zhou J, Duncan RS, El-Meanawy A, McCarthy ET, Sharma R, Johnson ML, 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
AnimalsDinoprostone
Female
Mechanotransduction, Cellular
Mice
Podocytes
Receptors, Prostaglandin E, EP2 Subtype
Renal Insufficiency, Chronic
Signal Transduction
Stress, Mechanical
