title: Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury.
abstract: Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.
authors.affiliation: Yale Univ. School of Medicine, PO Box 208029, New Haven, CT 06520. sarah.huen@yale.edu.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Huen
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Moeckel
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
mesh_terms: D000818:Animals; D005355:Fibrosis; D015151:Immunoblotting; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1
keywords: TGF-β1; ischemia-reperfusion; macrophage; renal fibrosis