title: Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells.
abstract: Transforming growth factor-β (TGF-β) strongly promotes renal tubulointerstitial fibrosis, but the cellular target that mediates its profibrotic actions has not been clearly identified. While in vitro data suggest that TGF-β-induced matrix production is mediated by renal fibroblasts, the role of these cells in TGF-β-dependent tubulointerstitial fibrosis following renal injury is not well defined. To address this, we deleted the TGF-β type II receptor in matrix-producing interstitial cells using two different inducible Cre models: COL1A2-Cre with a mesenchymal enhancer element and tenascin-Cre that targets medullary interstitial cells, and either the mouse unilateral ureteral obstruction or the aristolochic acid renal injury model. Renal interstitial cells lacking the TGF-β receptor had significantly impaired collagen I production, but, unexpectedly, overall tissue fibrosis was unchanged in the conditional knockouts after renal injury. Thus, abrogating TGF-β signaling in matrix-producing interstitial cells is not sufficient to reduce fibrosis after renal injury.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Surekha
authors.initials: S
authors.lastname: Neelisetty
authors.affiliation: Department of Pathology and Laboratory Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Alford
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Reynolds
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Woodbury
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Stellor
authors.initials: S
authors.lastname: Nlandu-Khodo
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Haichun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt Medical Center, Nashville, Tennessee, USA.|Department of Pediatrics, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.|Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Hao
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.|Department of Research, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.|Department of Research, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt Medical Center, Nashville, Tennessee, USA.|Department of Cell and Developmental Biology, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee, USA.|Department of Research, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.|Department of Cell and Developmental Biology, Vanderbilt Medical Center, Nashville, Tennessee, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Gewin
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D034341:Aristolochic Acids; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D000199:Actins; D034341:Aristolochic Acids; D024042:Collagen Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; C000228:aristolochic acid I; D020797:Receptor, Platelet-Derived Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II