title: Absence of nicotinic acetylcholine receptor α7 subunit amplifies inflammation and accelerates onset of fibrosis: an inflammatory kidney model.
abstract: Inflammation is regulated by endogenous mechanisms, including anti-inflammatory cytokines, adenosine, and the nicotinic acetylcholine receptor α7 subunit (α7nAChR). We investigated the role of α7nAChR in protection against the progression of tissue injury in a model of severe, macrophage-mediated, cytokine-dependent anti-glomerular basement membrane (GBM) glomerulonephritis (GN), in α7nAChR-deficient (α7(-/-)) mice . At d 7 after the injection of anti-GBM antibody, kidneys from α7(-/-) mice displayed severe glomeruli (P < 0.0001) and tubulointerstitial lesions (P < 0.001) compared to kidneys from WT mice. An important finding was the presence of severe glomerulosclerosis in α7(-/-) mice in this early phase of the disease. Kidneys of α7(-/-) mice showed greater accumulation of inflammatory cells and higher expression of chemokines and cytokines than did those of WT mice. In addition, in α7(-/-) fibrotic kidneys, the expression of fibrin, collagen, TGF-β, and tissue inhibitor of metalloproteinase (TIMP)-2 increased, and the expression of TIMP3 declined. The increase in counterregulatory responses to inflammation in α7(-/-) nephritic kidneys did not compensate for the lack of α7nAChR. These findings indicate that α7nAChR plays a key role in regulating the inflammatory response in anti-GBM GN and that disruption of the endogenous protective α7nAChR amplifies inflammation to accelerate kidney damage and fibrosis.
authors.affiliation: *Department of Pathology and Division of Nephrology, Department of Medicine, and The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA; and Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Luan D
authors.initials: LD
authors.lastname: Truong
authors.affiliation: *Department of Pathology and Division of Nephrology, Department of Medicine, and The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA; and Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Trostel
authors.affiliation: *Department of Pathology and Division of Nephrology, Department of Medicine, and The Methodist Hospital, Baylor College of Medicine, Houston, Texas, USA; and Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA gabriela.garcia@ucdenver.edu.
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Garcia
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D050533:Glomerular Basement Membrane / Q000378:metabolism* / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D021122:Protein Subunits / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D016207:Cytokines; D021122:Protein Subunits; D019717:Tissue Inhibitor of Metalloproteinase-3; D016212:Transforming Growth Factor beta; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019716:Tissue Inhibitor of Metalloproteinase-2; D005337:Fibrin; D003094:Collagen
keywords: chemokines; cytokines; macrophages