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1 Department of Medicine of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ottawa, Canada
2 Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital, Ottawa, Ontario, Canada; Department of Molecular Medicine, Ottawa Health Research Institute, Ottawa, Ottawa, Canada
3 Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital, Ottawa, Ontario, Canada; Department of Molecular Medicine, Ottawa Health Research Institute, Ottawa, Ottawa, Canada; Department of Medicine of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ottawa, Canada
* To whom correspondence should be addressed. E-mail: ckennedy{at}uottawa.ca.
A dynamic cytoskeleton allows podocytes to withstand significant mechanical stress upon elevation of intra-glomerular capillary pressure (Pgc). However, vasoactive hormones, such as prostaglandin E2 (PGE2), may challenge the integrity of the actin cytoskeleton, alter podocyte morphology, and compromise glomerular permeability. PGE2 synthesis correlates with the onset of proteinuria and increased Pgc following reduced nephron mass. We investigated the interplay between mechanical stress, cyclooxygenase (COX) and E-Prostanoid (EP) receptor expression, and the actin cytoskeleton, using an in vitro model of cell stretch. Immortalized mouse podocytes grown on flexible silicone membranes were cyclically stretched (5% elongation, 0.5 Hz) for 2 hr. EP4 and COX-2 mRNA increased 3- and 7-fold above non-stretched controls, whereas EP1 and COX-1 levels were unchanged. Six hr of stretch resulted in a 3-fold increase in PGE2-stimulated cAMP accumulation, a measure of EP4 receptor function, and an increase in COX-2 protein. The stretch-induced effects on COX-2 / EP4 expression and EP4-induced cAMP production were attributable to p38 MAP kinase, as blockade of this pathway, but not of ERK or JNK, abrogated the response. These stretch-induced changes in expression were transcriptionally-dependent as they were actinomycin D-sensitive. Finally, we investigated the influence of enhanced EP4 signaling on the actin cytoskeleton. Addition of PGE2 resulted in actin filament depolymerization observable only in stretched cells. Our results indicate that key components of the eicosanoid pathway are upregulated by mechanically-stimulated p38 MAP kinase in podocytes. Enhanced EP4 receptor signaling may undermine podocyte cytoskeletal dynamics and thereby compromise filtration barrier function under conditions of increased Pgc.
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