title: Distinct bone morphogenetic proteins activate indistinguishable transcriptional responses in nephron epithelia including Notch target genes.
abstract: Endogenous Bone Morphogenetic Protein (BMP) signaling plays a significant role in the kidney's recovery from acute injury and exogenous administration of BMP7 has therapeutic potential in numerous rodent models of renal injury and disease. However, in the healthy kidney endogenous BMP7 ligand is vigorously counteracted by extracellular antagonists such as USAG1 and CHRDL1. Little is known about the degree of BMP signaling and the ligands driving it in the healthy adult kidney. In this study we characterize basal BMP signaling in the healthy tubular nephron, and show that BMP2 is expressed in proximal nephron epithelial cells. Comparative 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. Interestingly, our gene profiling analysis shows that BMP signaling activates a number of Notch regulated transcription factors, including HEY1. As in other biological systems, HEY1 functions as a negative feedback regulator of BMP2 expression in the proximal tubule. In summary, this work reveals endogenous BMP signaling patterns in the healthy human and mouse kidneys, and identifies novel gene targets, some of which are involved in the complex regulation of BMP signaling in the adult kidney.
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, United States.
authors.forename: Barry W
authors.initials: BW
authors.lastname: Larman
authors.forename: Michele J
authors.initials: MJ
authors.lastname: Karolak
authors.forename: Volkhard
authors.initials: V
authors.lastname: Lindner
authors.forename: Leif
authors.initials: L
authors.lastname: Oxburgh
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D005136:Eye Proteins; D049410:Luciferases, Renilla; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D011994:Recombinant Proteins; D051785:Smad Proteins; C486602:CHRDL1 protein, human; C485631:HEY1 protein, human