title: Gremlin1 plays a key role in kidney development and renal fibrosis.
abstract: Gremlin1 (Grem1), an antagonist of bone morphogenetic proteins, plays a key role in embryogenesis. A highly specific temporospatial gradient of Grem1 and bone morphogenetic protein signaling is critical to normal lung, kidney, and limb development. Grem1 levels are increased in renal fibrotic conditions, including acute kidney injury, diabetic nephropathy, chronic allograft nephropathy, and immune glomerulonephritis. We demonstrate that a small number ofgrem1-/-whole body knockout mice on a mixed genetic background (8%) are viable, with a single, enlarged left kidney and grossly normal histology. Thegrem1-/-mice displayed mild renal dysfunction at 4 wk, which recovered by 16 wk. Tubular epithelial cell-specific targeted deletion of Grem1 (TEC-grem1-cKO) mice displayed a milder response in the acute injury and recovery phases of the folic acid model. Increases in indexes of kidney damage were smaller inTEC-grem1-cKOthan wild-type mice. In the recovery phase of the folic acid model, associated with renal fibrosis,TEC-grem1-cKOmice displayed reduced histological damage and an attenuated fibrotic gene response compared with wild-type controls. Together, these data demonstrate that Grem1 expression in the tubular epithelial compartment plays a significant role in the fibrotic response to renal injury in vivo.
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Church
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Imran
authors.initials: I
authors.lastname: Ali
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Mitchel
authors.initials: M
authors.lastname: Tate
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Lavin
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Arjun
authors.initials: A
authors.lastname: Krishnakumar
authors.affiliation: Utrecht Medical Centre, Utrecht, The Netherlands.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Kok
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Hombrebueno
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Dunne
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
authors.forename: Victoria
authors.initials: V
authors.lastname: Bingham
authors.affiliation: Utrecht Medical Centre, Utrecht, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Conway Institute, University College Dublin, Dublin, Ireland; and.
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom; d.brazil@qub.ac.uk.
authors.forename: Derek P
authors.initials: DP
authors.lastname: Brazil
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005492:Folic Acid; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038081:Organogenesis; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D014564:Urogenital Abnormalities / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines
chemical_list: D005492:Folic Acid; D036341:Intercellular Signaling Peptides and Proteins; C113178:Grem1 protein, mouse; D016207:Cytokines
keywords: Gremlin; development; kidney; renal fibrosis