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

DOI to cite this document:: 10.5283/epub.52094

Fuchs, Michaela A. A.

; Schrankl, Julia ; Leupold, Christina ; Wagner, Charlotte ; Kurtz, Armin ; Broeker, Katharina A.-E.

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Date of publication of this fulltext: 07 Apr 2022 04:31

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Cyclooxygenase (Cox) inhibitors are known to have severe side effects during renal development. These consist of reduced re-nal function, underdeveloped subcapsular glomeruli, interstitialfibrosis, and thinner cortical tissue. Global genetic deletion ofCox-2 mimics the phenotype observed after application of Cox inhibitors. This study aimed to investigate which cell typesexpress Cox-2 and prostaglandin E2receptors 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 FoxD1þstromal progenitors; EP1 andEP3, on the other hand, were expressed in tubules. Cox-2 mRNA was detected in medullary interstitial cells and macula densacells. Functional investigations were performed with a cell-specific approach to delete Cox-2, EP2, and EP4 in FoxD1þstromalprogenitor cells. Our data show that Cox-2 expression in macula densa cells is sufficient to drive renal development. Deletion ofEP2 or EP4 in FoxD1þcells had no functional effect on renal development. Codeletion of EP2 and EP4 in FoxD1þstromal cells,however, led to severe glomerular defects and a strong decline of glomerularfiltration rate (1.316 ± 69.7mL/min/100 g body wt incontrols vs. 644.1 ± 64.58mL/min/100 g body wt in FoxD1þ/CreEP2⁻/⁻EP4ffmice), similar to global deletion of Cox-2.Furthermore, EP2/EP4-deficient mice showed a significant increase in collagen production with a strong downregulation of renalrenin expression. This study shows the distinct localization of EP receptors in mice. Functionally, we could identify EP2 and EP4receptors in stromal FoxD1þprogenitor 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 isunclear in which cells Cox-2 and the receptors for prostaglandin E2(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 stro-mal progenitor cells may require intact prostaglandin E2signaling through EP2 and EP4 receptors for normal renal development.

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