Prostaglandins as Regulators of Nephrogenesis

Despite several discoveries furthering our understanding of nephrogenesis, the factors that influence cell fate decisions within the nephron remain largely unknown. The zebrafish, Danio rerio, forms a simple embryonic kidney organized in a proximal-distal pattern of contiguous segments homologous to the human nephron. Here, we performed a multiplex chemical genetic screen using zebrafish embryos to determine factors that regulate proximal and distal nephron fate choices. Employing this method, we identified prostaglandins as a major player in nephrogenesis, which have been previously shown to dictate liver versus pancreas cell fate decisions. We found that prostaglandin agonists restricted distal segment formation and expanded the proximal segment lineage during nephrogenesis. Genetic abrogation or inhibition of the prostaglandin producing enzymes, Prostaglandin-endoperoxide synthase 1 or 2a (also known as Cox-1/Ptgs1 and Cox-2/Ptgs2a respectively), or the Prostaglandin E receptor 2a or 4a (Ptger2a, Ptger4a), which we found to be expressed in renal progenitors, triggered an alteration in the balance of distal segment fates. Of particular note, distal segment fate in Ptgs1 or Ptgs2a deficient embryos was rescued by exogenous prostaglandin treatment. Further, we saw that overexpression or inhibition of the prostaglandin pathway significantly altered the renal progenitor expression domains, sim1a, irx3b, and mecom, which are necessary for proximal and distal tubule patterning. Epistasis studies suggest that prostaglandin signaling functions upstream of these transcription factors. Taken together, these findings show for the first time that prostaglandin signaling is an essential component of nephron cell fate choice, and indicate that the prostaglandin family may have considerable implications in understanding how to treat kidney failure that arise from congenital kidney diseases and end-stage renal disease.