Intact prostaglandin signaling through EP2 and EP4 receptors in stromal progenitor cells is required for normal development of the renal cortex in mice.

Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901990 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1466 (Electronic) Linking ISSN: 15221466 NLM ISO Abbreviation: Am J Physiol Renal Physiol Subsets: MEDLINE

Original Publication: Bethesda, Md. : American Physiological Society, c1997-

Cyclooxygenase 2/*metabolism ; Kidney Cortex/*enzymology ; Prostaglandins/*metabolism ; Receptors, Prostaglandin E, EP2 Subtype/*metabolism ; Receptors, Prostaglandin E, EP4 Subtype/*metabolism ; Stem Cells/*metabolism ; Stromal Cells/*enzymology; Animals ; Cyclooxygenase 2/genetics ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation, Developmental ; Kidney Cortex/cytology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Organogenesis ; Receptors, Prostaglandin E, EP2 Subtype/genetics ; Receptors, Prostaglandin E, EP4 Subtype/genetics ; Signal Transduction ; Mice

Cyclooxygenase (Cox) inhibitors are known to have severe side effects during renal development. These consist of reduced renal function, underdeveloped subcapsular glomeruli, interstitial fibrosis, and thinner cortical tissue. Global genetic deletion of Cox-2 mimics the phenotype observed after application of Cox inhibitors. This study aimed to investigate which cell types express Cox-2 and prostaglandin E 2 receptors and what functions are mediated through this pathway during renal development. Expression of EP2 and EP4 mRNA was detected by RNAscope mainly in descendants of FoxD1 ⁺ stromal progenitors; EP1 and EP3, on the other hand, were expressed in tubules. Cox-2 mRNA was detected in medullary interstitial cells and macula densa cells. Functional investigations were performed with a cell-specific approach to delete Cox-2, EP2, and EP4 in FoxD1 ⁺ stromal progenitor cells. Our data show that Cox-2 expression in macula densa cells is sufficient to drive renal development. Deletion of EP2 or EP4 in FoxD1 ⁺ cells had no functional effect on renal development. Codeletion of EP2 and EP4 in FoxD1 ⁺ stromal cells, however, led to severe glomerular defects and a strong decline of glomerular filtration rate (1.316 ± 69.7 µL/min/100 g body wt in controls vs. 644.1 ± 64.58 µL/min/100 g body wt in FoxD1 ^+/Cre EP2 ^-/- EP4 ^ff mice), similar to global deletion of Cox-2. Furthermore, EP2/EP4-deficient mice showed a significant increase in collagen production with a strong downregulation of renal renin expression. This study shows the distinct localization of EP receptors in mice. Functionally, we could identify EP2 and EP4 receptors in stromal FoxD1 ⁺ progenitor cells as essential receptor subtypes for normal renal development. NEW & NOTEWORTHY Cyclooxygenase-2 (Cox-2) produces prostaglandins that are essential for normal renal development. It is unclear in which cells Cox-2 and the receptors for prostaglandin E 2 (EP receptors) are expressed during late nephrogenesis. This study identified the expression sites for EP subtypes and Cox-2 in neonatal mouse kidneys. Furthermore, it shows that stromal progenitor cells may require intact prostaglandin E 2 signaling through EP2 and EP4 receptors for normal renal development.

Keywords: cyclooxygenase-2; interstitial cells; prostaglandin receptors; renal development; renal function

figshare 10.6084/m9.figshare.17313557

0 (Forkhead Transcription Factors)
0 (Foxd1 protein, mouse)
0 (Prostaglandins)
0 (Ptger2 protein, mouse)
0 (Ptger4 protein, mouse)
0 (Receptors, Prostaglandin E, EP2 Subtype)
0 (Receptors, Prostaglandin E, EP4 Subtype)
EC 1.14.99.- (Ptgs2 protein, mouse)
EC 1.14.99.1 (Cyclooxygenase 2)

Date Created: 20220117 Date Completed: 20220307 Latest Revision: 20240226

20240226

10.1152/ajprenal.00414.2021

35037469