Prostaglandins regulate growth and transport in cultured renal cells

Prostaglandins (PGs) are major regulators of growth and transport in kidney tubule epithelial cells. Although the kidney is a major producer of prostaglandins, little is understood about prostaglandin effects on tubule epithelial cells, and the signaling mechanisms involved in these effects. Our approach has been the use of in vitro kidney tubule epithelial cell culture systems in hormonally defined, serum free medium. We have found that Prostaglandin E₁ (PGE₁) and PGE₂ stimulate both growth and ion transport by an established kidney epithelial cell line, Madin Darby Canine Kidney, a distal tubule model. Similar affects on growth were observed with primary baby mouse kidney epithelial cells, indicating their physiologic significance. Subsequent to these studies, the overproduction of PGE₂ in the tumor microenvironment has been found to contribute to the formation of a number of carcinomas. This is because PGE₂ stimulates the growth of many types of epithelial cells in vivo. We have also found that PGE₁ and PGE₂ stimulate the Na,K-ATPase in MDCK cells, as well as primary rabbit kidney proximal tubule cells. Regulatory effects of PGE₁ and PGE₂ on Na,K-ATPase were attributed to transcriptional control. Prostaglandin Response Elements (PGREs) were identified on the Na,K-ATPase beta subunit promoter. These PGREs are highly conserved elements present on genomic DNA in a number of species. In addition, we have identified a novel regulatory mechanism for gene expression via these PGREs. Both cyclic AMP Regulatory Element Binding Protein (CREB) and Sp1 bind to PGREs, and interact so as to modulate the rate of transcription. The molecular mechanisms underlying the CREB/Sp1 interaction are being defined.