title: Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease.
abstract: The bone morphogenetic proteins (BMPs) profoundly affect embryonic development, differentiation and disease. BMP signaling is suppressed by cysteine-rich domain proteins, such as chordin, that sequester ligands from the BMP receptor. We describe a novel protein, KCP, with 18 cysteine-rich domains. Unlike chordin, KCP enhances BMP signaling in a paracrine manner. Smad1-dependent transcription and phosphorylated Smad1 (P-Smad1) levels are increased, as KCP binds to BMP7 and enhances binding to the type I receptor. In vivo, Kcp(-/-) mice are viable and fertile. Because BMPs have a pivotal role in renal disease, we examined the phenotype of Kcp(-/-) mice in two different models of renal injury. Kcp(-/-) animals show reduced levels of P-Smad1, are more susceptible to developing renal interstitial fibrosis, are more sensitive to tubular injury and show substantial pathology after recovery. The data indicate an important role for KCP in attenuating the pathology of renal fibrotic disease.
authors.affiliation: Department of Pathology, University of Michigan, 1301 Catherine Street, Ann Arbor, Michigan 48109, USA.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Lin
authors.forename: Sanjeevkumar R
authors.initials: SR
authors.lastname: Patel
authors.forename: Xu
authors.initials: X
authors.lastname: Cheng
authors.forename: Eun Ah
authors.initials: EA
authors.lastname: Cho
authors.forename: Inna
authors.initials: I
authors.lastname: Levitan
authors.forename: Matthew
authors.initials: M
authors.lastname: Ullenbruch
authors.forename: Sem H
authors.initials: SH
authors.lastname: Phan
authors.forename: John M
authors.initials: JM
authors.lastname: Park
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Dressler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D003545:Cysteine; D004268:DNA-Binding Proteins / Q000378:metabolism; D005136:Eye Proteins / Q000494:pharmacology; D005355:Fibrosis / Q000517:prevention & control*; D007668:Kidney / Q000473:pathology*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000494:pharmacology; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000378:metabolism; D029867:Xenopus Proteins / Q000494:pharmacology
chemical_list: C486602:CHRDL1 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; C409025:KCP protein, Xenopus; D009419:Nerve Tissue Proteins; D011506:Proteins; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D015534:Trans-Activators; D029867:Xenopus Proteins; C501622:kielin-chordin-like protein, mouse; D003545:Cysteine