Absence of nicotinic acetylcholine receptor alpha 7 subunit amplifies inflammation and accelerates onset of fibrosis: an inflammatory kidney model

摘要

Inflammation is regulated by endogenous mechanisms, including anti-inflammatory cytokines, adenosine, and the nicotinic acetylcholine receptor alpha 7 subunit (alpha 7nAChR). We investigated the role of alpha 7nAChR in protection against the progression of tissue injury in a model of severe, macrophage-mediated, cytokine-dependent antiglomerular basement membrane (GBM) glomerulonephritis (GN), in alpha 7nAChR-deficient (alpha 7(-/-)) mice. At d 7 after the injection of anti-GBM antibody, kidneys from alpha 7(-/-) 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 alpha 7(-/-) mice in this early phase of the disease. Kidneys of alpha 7(-/-) mice showed greater accumulation of inflammatory cells and higher expression of chemokines and cytokines than did those of WT mice. In addition, in alpha 7(-/-)fibrotic kidneys, the expression of fibrin, collagen, TGF-beta, and tissue inhibitor of metalloproteinase (TIMP)-2 increased, and the expression of TIMP3 declined. The increase in counterregulatory responses to inflammation in alpha 7(-/-) nephritic kidneys did not compensate for the lack of alpha 7nAChR. These findings indicate that alpha 7nAChR plays alpha key role in regulating the inflammatory response in anti-GBM GN and that disruption of the endogenous protective alpha 7nAChR amplifies inflammation to accelerate kidney damage and fibrosis.