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Published ahead of print on April 8, 2009
J Am Soc Nephrol 20: 1020-1031, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008070768
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BASIC RESEARCH

Chordin-like 1 and Twisted Gastrulation 1 Regulate BMP Signaling following Kidney Injury

Barry W. Larman, Michele J. Karolak, Derek C. Adams and Leif Oxburgh

Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine

Correspondence: Dr. Leif Oxburgh, Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074. Phone: 207-885-8115; Fax: 207-885-8110; E-mail: oxburl{at}mmc.org

Received for publication July 22, 2008. Accepted for publication December 16, 2008.

Stimulation of the bone morphogenetic protein (BMP) pathway protects the kidney from acute and chronic injury. Numerous regulators in the kidney control BMP signaling, offering many targets for therapeutic manipulation. Here, we screened for modulators of BMP signaling in the ischemia-sensitive S3 segment and found that Chordin-like 1 is expressed in this segment of both the mouse and human nephron. Chordin-like 1 specifically antagonizes BMP7, which is expressed in the neighboring distal nephron, and this depends on the presence of the protein Twisted gastrulation. Upon ischemia-induced degeneration of the S3 segment, we observed a reduction in Chordin-like 1 expression coincident with intense BMP signaling in tubules of the recovering kidney. Restored expression accompanied proximal tubule epithelia redifferentiation, again coincident with decreased BMP signaling. We propose that Chordin-like 1 reduces BMP7 signaling in healthy proximal tubules, and the loss of this activity upon sloughing of injured epithelia promotes BMP7 signaling in repopulating, dedifferentiated epithelia. As regenerating epithelia differentiate, Chordin-like 1 is again expressed, antagonizing BMP7. These data suggest a mechanism for dynamic regulation of renoprotective BMP7 signaling in the S3 segment of the proximal tubule.


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