Transgenic Mice Overexpressing the Complement Inhibitor Crry as a Soluble Protein Are Protected from Antibody-induced Glomerular Injury

• DOI: 10.1084/jem.188.7.1321
• Publication Date: 2002-07-26T16:49:30Z
• Authors: Richard J. Quigg; Chun He; Alice Lim; Dawn Berthiaume; Jessy J. Alexander; Damian Kraus; V. Michael Holers
• Keywords: Nephrotoxicity

Complement receptor 1–related gene/protein y (Crry) is a potent murine membrane complement regulator that inhibits classical and alternative pathway C3 convertases. In nephrotoxic serum (NTS) nephritis, injected antibodies (Abs) bind to glomeruli, leading activation subsequent glomerular injury albuminuria. To study the phenotypic effects of continuous blockade, transgenic mice were created express recombinant soluble (rs) Crry directed by broadly active heavy metal-inducible metallothionein-I promoter. One line expressing high levels rsCrry was propagated. Serum 18.7 ± 2.7 μg/ml (n = 5) at basal level increased 118.1 20.6 4 d after addition zinc drinking water. By reverse transcription polymerase chain reaction (RT-PCR), transgene messenger (m)RNA present in liver, kidney, brain, lung, spleen, but not heart. situ RT-PCR analysis kidneys, mRNA widely expressed both renal glomeruli tubules. Urinary excretion 113.4 22.4 with fractional relative creatinine 13.2 2.7%, consistent local production secretion into urine. The founder all positive adult animals have remained healthy no mortality or apparent abnormalities, including infection immune complex disease. determine whether blocked complement-mediated injury, NTS nephritis induced injection immunoglobulin (Ig)G, followed an 18-h urine collection quantitate albumin as measure injury. transgene-negative littermates 15), transgene-positive 10), fed albuminuria 4,393 948, 1,783 454, 1,057 277 μg/mg creatinine, respectively (P < 0.01 ANOVA). Glomerular evident immunofluorescence staining 12/15 animals, none zinc. Thus, we produced first overexpress convertase inhibitor. expression markedly ameliorates Ab-induced disease model vivo. These results support hypothesis inhibition step feasible effective states.