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Absence of nicotinic acetylcholine receptor α7 subunit amplifies inflammation and accelerates onset of fibrosis: an inflammatory kidney model
Author(s) -
Truong Luan D.,
Trostel Jessica,
Garcia Gabriela E.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-262493
Subject(s) - inflammation , fibrosis , kidney , glomerulonephritis , glomerulosclerosis , medicine , chemokine , ccl2 , endocrinology , proteinuria
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 d7 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.—Truong, L. D., Trostel. J., Garcia, G. E. Absence of nicotinic acetylcholine receptor α7 subunit amplifies inflammation and accelerates onset of fibrosis: an inflammatory kidney model. FASEB J. 29, 3558‐3570 (2015). www.fasebj.org