Overexpression of complement inhibitor Crry does not prevent cryoglobulin-associated membranoproliferative glomerulonephritis

Anja S Mühlfeld, Stephan Segerer, Kelly Hudkins, Andrew G Farr, Lihua Bao, Damian Kraus, V Michael Holers, Richard J Quigg, Charles E Alpers
Kidney International 2004, 65 (4): 1214-23

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.

CONCLUSION: 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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"