Absence of nicotinic acetylcholine receptor a7 subunit amplifies inflammation and accelerates onset of fibrosis: An inflammatory kidney model

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 amodel of severe, macrophage-mediated, cytokine-dependent antiglomerular 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 fromWTmice. 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.