Date of Award

12-2011

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

Advisor

Leif Oxburgh

Second Committee Member

Volkhard Lindner

Third Committee Member

Igor Prudovsky

Abstract

Endogenous Bone Morphogenetic Protein ("BMP") plays a significant role in renal recovery from acute injury. Moreover, the therapeutic administration of BMP7 has shown benefit in numerous rodent models of renal injury and disease. Renal BMP signaling is controlled by numerous regulators which present potential therapeutic targets. Here, screening for such modulators in the ischemia-sensitive S3 segment of the mouse nephron identified the unique expression of Chordin-like 1 ("CHRDL1"). The data show the antagonistic properties of CHRDL1 are specific for BMP7, a BMP expressed in neighboring distal tubules. CHRDL1 expression is temporarily lost following ischemic injury and this coincides with intense BMP signaling in tubules of the recovering kidney. I propose that CHRDL1 reduces BMP7 signaling in healthy proximal tubules, and that its loss upon injury promotes BMP signaling in recovering epithelia. Upon regeneration of nephron epithelia, CHRDL1 expression returns, re-exerting its antagonistic effect upon BMP7. CHRDL1's specificity for BMP7, a BMP not produced in the proximal tubule, raises the questions of whether the proximal tubule is producing other BMPs, and if so, why they are not antagonized by CHRDL1. The data show that proximal tubule expresses BMP2 and BMP4 and maintains high levels of homeostatic BMP signaling. Gene profiling of proximal tubule cell responses to BMP2 and BMP7 does not reveal any qualitative difference, suggesting that identical BMP gene targets may be activated in healthy and injured organs. Profiling analysis demonstrates the activation of transcription factors typically associated with Notch signaling, including HEY1. The data suggest that this protein may function as a negative feedback regulator of BMP2 expression. Finally, a number of novel genes regulated by proximal tubule cells in response to BMP are identified. Investigating these candidates may supplement existing knowledge regarding the mechanisms through which BMPs achieve their renoprotective and therapeutic effect.

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