Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis.
BACKGROUND
Mice overexpressing thymic stromal lymphopoietin (TSLP) develop mixed cryoglobulinemia with renal disease closely resembling human cryoglobulin-associated membranoproliferative glomerulonephritis (MPGN), including glomerular deposits of immunoglobulins and complement. We assessed the effect of complement inhibition through overexpression of Crry (complement receptor-1 related gene/protein Y), which blocks the classic and alternative pathway of complement activation through inhibition of the C3 convertase, in cryoglobulinemia-associated immune complex glomerulonephritis.


METHODS
TSLP transgenic mice were crossbred with animals overexpressing Crry. Mice were sacrificed after 50 days (females) or 120 days (males), and kidneys, blood, and urine were collected from seven mice of each experimental group (wild type, Crry transgenic, TSLP transgenic, and Crry/TSLP doubly transgenic).


RESULTS
TSLP/Crry doubly transgenic animals demonstrated expected serum levels of Crry. Renal involvement, both in TSLP transgenic and TSLP/Crry doubly transgenic animals, was characterized by glomerular matrix expansion, macrophage influx, activation of mesangial cells, and deposition of immunoglobulins and complement. Overexpression of Crry did not result in significant improvement of renal pathology or laboratory findings. Expression of recombinant soluble Crry was confirmed by enzyme-linked immunosorbent assay (ELISA) in Crry transgenic animals. However, formation of the membrane attack complex C5b-9 as a marker of terminal active complement components and represented by glomerular C9 staining could not be inhibited in Crry transgenic TSLP mice.


CONCLUSIONS
These results indicate that overexpression of Crry was not sufficient to prevent renal injury in TSLP transgenic mice. We suggest that the inhibitory capacity of Crry may be overwhelmed by chronic complement activation. Further studies need to address the role of complement in cryoglobulinemic glomerulonephritis before therapeutic complement inhibition can be attempted.
Mühlfeld
Anja S
AS
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Segerer
Stephan
S
Hudkins
Kelly
K
Farr
Andrew G
AG
Bao
Lihua
L
Kraus
Damian
D
Holers
V Michael
VM
Quigg
Richard J
RJ
Alpers
Charles E
CE
D000818:Animals; D002455:Cell Division; D003176:Complement C3 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism; D003450:Cryoglobulins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000503:physiopathology / Q000517:prevention & control*; D007136:Immunoglobulins / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011951:Receptors, Complement / Q000378:metabolism*; D017463:Receptors, Complement 3b; D000094632:Thymic Stromal Lymphopoietin
D003176:Complement C3; D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D003450:Cryoglobulins; D016207:Cytokines; D007136:Immunoglobulins; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003165:Complement System Proteins; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse