To date, the downstream effects of changes in tubular flow rate (and its hydrodynamic consequences) on intracellular signaling, gene transcription and protein translation in tubular epithelial cells are largely unknown. In preliminary studies, the Biomechanical Renal Physiology Laboratory demonstrates that increases in perfusate flow across the surface (generating fluid shear stress [FSS]) of IMCD3 cells induces robust prostaglandin E2 (PGE2) secretion and cyclooxygenase-2 (COX-2; encoded by ptgs-2) mRNA expression.
Pretreatment of IMCD3 cells with mitogen activated protein kinase (MAPK) inhibitors reduces flow-mediated COX-2 mRNA expression. We also show that the concentration of adenosine is greater in media from sheared cells compared static cells.
Finally, we demonstrate in isolated microperfused native CDs that inhibition of PGE2 synthesis only augments flow-stimulated Na transport, but not basal Na transport.
Thus, we hypothesize that increases in tubular flow rate trigger nucleotide secretion and purinergic signaling, specifically increasing [Ca2+]i and MAPK activation, in renal tubular epithelia, and that activation of these pathways regulate the synthesis of ptgs-2 mRNA and PGE2 production which influences Na balance.
Additionally, polycystic kidney diseases (PKD), including autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD), are characterized histopathologically by hyperproliferative cystic renal epithelium and clinically by aquaresis. Recent observations suggest that altered prostanoid production contributes to these pathologic and clinical features.
We hypothesize that aberrant expression of prostaglandin E2 and its receptors in PKD epithelia contributes to the proliferative phenotype of cystic epithelia in both ADPKD and ARPKD through activation of Gs coupled EP receptors that induce -catenin signaling.
Rajeev Rohatgi, MD
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