Retinoic acid-inducible prostaglandin I2 receptor is required for the development of proximal tubules in zebrafish.

The nephron comprises specialized segments, such as the glomerulus and tubules, and is the structural and functional unit of the kidney. Nephron formation in development is important for subsequent normal nephric function. However, mechanisms regulating the nephron segment formation (nephron segmentation) remain unclear. Here, we report that the prostaglandin (PG) I2-IP receptor is required for the development of proximal tubules in zebrafish. We identified expression of the IP receptor in the proximal tubules during nephron segmentation. This expression was abolished by an inhibitor of retinoic acid (RA) synthases and antagonists of RA nuclear receptors. The loss of IP receptor expression induced by the RA synthase inhibitor was restored by the addition of RA. These results suggest that RA induces IP receptor expression in the proximal tubules during nephron segmentation through RA nuclear receptors. Intriguingly, knockout of the IP receptor caused impaired differentiation into proximal tubule cells and nephric multiciliated cells, an aberrant balance between proximal and distal tubules, and abnormal kidney function, which are similar to the phenomena observed by inhibition of RA signaling during nephron segmentation. Consistently, inhibition of PG synthesis by an inhibitor of PG synthases caused impaired differentiation into proximal tubule cells and nephric multiciliated cells and the aberrant balance between proximal and distal tubules. These impairments and the aberrant balance between the tubules were restored by the addition of an IP receptor agonist. Therefore, these findings highlight that the PGI2-IP receptor plays a crucial role in nephron segmentation downstream of RA signaling in proximal tubules.