Individuals born with low renal reserves are predisposed to progressive renal disease and primary hypertension as adults. Experimental evidence for vitamin A (retinol) control of nephrogenesis have led some to propose that maternal vitamin A status during pregnancy is responsible for most of the inborn variation in nephron number in the general population. The extent of collecting duct (CD) arborization during development is a primary determinant of nephron endowment. In the present study, the hypothesis of direct retinoic acid (RA) effects on CD branching morphogenesis was tested using murine inner medullary collecting duct (mIMCD-3) cells. Data presented show that mIMCD-3 cells express retinoic acid receptors (RARs) which mediate up to 30-fold induction of reporter activity from RARE-luciferase in transient transfection. In deep collagen culture, the RAR-selective agonist TTNPB and physiological levels of all-trans RA dramatically increase the number and length of branching tubules formed compared to control. Although retinoid regulation of EGF-R is well established in other cell lines, quantitative PCR and [125-I] EGF binding analysis of retinoid-treated cells provide no evidence of RA regulation of EGF-R transcripts or numbers at the cell surface. However, the cancellation of RA effects by the EGF-R inhibitor tyrphostin AG1478 suggests participation of active EGF-R in downstream signaling pathways; the possibility of receptor cross-talk by RA transactivation of EGF-R is raised. mIMCD-3 is a retinoid-responsive cell line whose branching program is strongly induced by RA. Identification of retinoid targets may have both fundamental and applied relevance, offering potential insight to in vivo processes, and as basic technology supporting tubular engineering and potential artificial renal replacement therapy.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.79124 |
| Date | January 2003 |
| Creators | Sheu, Carey |
| Contributors | Goodyer, Paul R. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001975014, proquestno: AAIMQ88293, Theses scanned by UMI/ProQuest. |
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