Progesterone induced mesenchymal differentiation and rescued cystic dilation of renal tubules of Pkd1−/− mice

• Published in: Biochemical and biophysical research communications 2012-08, Vol.425 (2), p.212-218
• Main Authors: Wachi, Tomoka, Yoshida, Noriyuki, Funae, Yoshihiko, Ueno, Munehisa, Germino, Gregory G., Hirotsune, Shinji, Deguchi, Nobuhiro
• Format: Article
• Language: English
• Subjects: Animals; autosomal dominant polycystic kidney disease; Cell Differentiation - drug effects; cell membranes; Cysts - embryology; Cysts - genetics; Cysts - prevention & control; Differentiation; Dilatation, Pathologic - embryology; Dilatation, Pathologic - prevention & control; epithelial cells; Female; females; Gene expression; genes; genetic disorders; Kidney Tubules - abnormalities; mechanoreceptors; Mesoderm - cytology; Mesoderm - drug effects; Mice; Mice, Mutant Strains; mutation; organ culture; patients; Polycystic kidney; Polycystic Kidney, Autosomal Dominant - embryology; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - prevention & control; polycystins; Pregnancy; progesterone; Progesterone - administration & dosage; renal tubules; TRPP Cation Channels - genetics
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2012.07.070

► Impaired differentiation preceded in Pkd1−/− mice. ► Progesterone facilitated mesenchymal differentiation. ► Progesterone prevented cystic formation in Pkd1−/− kidneys. Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary disease affecting the kidneys, is caused in 85% of cases by mutations in the PKD1 gene. The protein encoded by this gene, polycystin-1, is a renal epithelial cell membrane mechanoreceptor, sensing morphogenetic cues in the extracellular environment, which regulate the tissue architecture and differentiation. However, how such mutations result in the formation of cysts is still unclear. We performed a precise characterization of mesenchymal differentiation using PAX2, WNT4 and WT1 as a marker, which revealed that impairment of the differentiation process preceded the development of cysts in Pkd1−/− mice. We performed an in vitro organ culture and found that progesterone and a derivative thereof facilitated mesenchymal differentiation, and partially prevented the formation of cysts in Pkd1−/− kidneys. An injection of progesterone or this derivative into the intraperitoneal space of pregnant females also improved the survival of Pkd1−/− embryos. Our findings suggest that compounds which enhance mesenchymal differentiation in the nephrogenesis might be useful for the therapeutic approach to prevent the formation of cysts in ADPKD patients.