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p38 MAP kinase mediates mechanically induced COX-2 and PG EP₄ receptor expression in podocytes: implications for the actin cytoskeleton

¹Kidney Research Centre, Division of Nephrology, Department of Medicine, The Ottawa Hospital, ³Ottawa Health Research Institute, and ²Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5

Submitted 16 September 2003 ; accepted in final form 5 December 2003

A dynamic cytoskeleton allows podocytes to withstand significant mechanical stress on elevation of intraglomerular capillary pressure (P_gc). 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 P_gc following reduced nephron mass. We investigated the interplay among mechanical stress, cyclooxygenase (COX), 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 h. EP₄ and COX-2 mRNA increased three- and sevenfold above nonstretched controls, whereas EP₁ and COX-1 levels were unchanged. Six hours of stretch resulted in a threefold 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 P_gc.

eicosanoids; adenosine 3',5'-cyclic monophosphate; mechanical stimulation

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