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Local extravascular pool of C3 is a determinant of postischemic acute renal failure
Author(s) -
Farrar Conrad A.,
Zhou Wuding,
Lin Tao,
Sacks Steven H.
Publication year - 2006
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.05-4747com
Subject(s) - isograft , complement system , compartment (ship) , medicine , ischemia , complement (music) , kidney , transplantation , pathology , immunology , chemistry , immune system , biochemistry , oceanography , complementation , gene , phenotype , geology
ABSTRACT The third complement component (C3) is an acute phase protein that plays a central role in reperfusion injury in several organ models. To investigate the contribution of local synthesis of C3 and distinguish it from that of circulating complement mainly produced by hepatic synthesis, we employed a mouse renal isograft model. Our model demonstrated a close relationship between the extent of intrarenal expression of C3 and cold‐ischemia induced injury. Ischemic C3‐positive donor kidneys transplanted into C3‐positive or C3‐negative recipients developed widespread tissue damage and severe acute renal failure. In contrast, ischemic C3‐negative isografts exhibited only mild degrees of functional and structural disturbance, even when transplanted into normal C3‐positive recipients. Thus local synthesis of C3, mostly identified in the tubular epithelium, was essential for complement‐mediated reperfusion damage, whereas circulating C3 had a negligible effect. Our results suggest a two‐compartment model for the pathogenic function of C3, in which the extravascular compartment is the domain of local synthesis of C3, and where the role of circulating C3 is redundant. Our data cast new light on the mechanism of complement‐mediated tissue injury in nonimmunological disorders, and challenges the long‐standing dogma that circulating components are the main complement effectors of extravascular tissue damage.—Farrar, C. A., Zhou, W., Lin, T., Sacks, S. H. Local extravascular pool of C3 is a determinant of postischemic acute renal failure. FASEB J. 20, 217–226 (2006)