All Phenotypes C3<tm2(C3)Lgmo> MGI Mouse

mortality/aging

premature death ( J:369997 )

• spontaneous mortality is seen, with a median age of survival of about 16 weeks

• mice administered anti-C5 antibody show improved survival rate, with 13 of 16 mice surviving compared to 3 of 16 mice on isotype-control treatment surviving, however withdrawal of anti-C5 mAb treatment after 16 weeks results in mice succumbing to the disease

• mice treated with anti-C5 mAb for 24 weeks show improved survival, with about 30% mortality

• mice treated with anti-C3b antibodies show improved survival rate, with 13 of 14 mice surviving compared to 3 of 14 on isotype control mAb treatment

• mice treated with anti-CFB antibodies show improved survival rate, with 16 of 17 mice surviving compared to 3 of 17 on isotype control mAb treatment

renal/urinary system

abnormal urine albumin level ( J:369997 )

• elevation in urinary albumin (normalized to urinary creatinine), indicting glomerular injury

hemoglobinuria ( J:369997 )

hematuria ( J:369997 )

• increase in urinary hemoglobin which suggests hematuria

abnormal podocyte foot process morphology ( J:369997 )

• increase in podocyte foot process width

• decrease in foot process number

podocyte foot process effacement ( J:369997 )

abnormal renal glomerulus basement membrane morphology ( J:369997 )

• the glomerular basement membrane contains electron-lucent subendothelial spaces (rarefactions), with or without flocculent material

increased renal glomerulus basement membrane thickness ( J:369997 )

• thickening and contortion of the glomerular basement membrane

abnormal renal glomerulus morphology ( J:369997 )

• kidneys show multiple glomerular lesions, including membranoproliferative glomerulopathy, hypertrophy of mesangial cells, segmental to global glomerular sclerosis, fibrin deposition with necrosis and leukocyte infiltration, and epithelial crescents

• mice treated with anti-C5 mAb for 24 weeks show a reduction in glomerular hypertrophy, glomerular and tubular injury score, and neutrophil and macrophage infiltration

abnormal glomerular endothelium fenestra morphology ( J:369997 )

• endothelium with a reduction in fenestrae

abnormal glomerular mesangium morphology ( J:369997 )

• mesangium is expanded

• both mesangial and subepithelial electron-dense deposits are seen

abnormal mesangial cell morphology ( J:369997 )

• hypertrophy of mesangial cells

expanded mesangial matrix ( J:369997 )

glomerulosclerosis ( J:369997 )

• segmental to global glomerular sclerosis

glomerular crescent ( J:369997 )

renal glomerular immunoglobulin deposits ( J:369997 )

• a little IgG deposition in seen in the glomeruli, which could be secondary to tissue damage and subsequent neoepitope generation or vascular leak

abnormal renal tubule morphology ( J:369997 )

• kidneys show tubular and interstitial changes consistent with tubular necrosis, degeneration, and tubulitis

renal tubular necrosis ( J:369997 )

kidney failure ( J:369997 )

• elevation in BUN and sCysC, markers of glomerular infiltration, indicating failing kidneys

• mice dosed with anti-C5, anti-C3b, or anti-CFB antibodies show improvement in kidney function, as measured by BUN and sCysC

liver/biliary system

bile duct hyperplasia ( J:369997 )

• livers show bile duct hyperplasia

liver inflammation ( J:369997 )

• livers show inflammation in the portal region

homeostasis/metabolism

increased blood urea nitrogen level ( J:369997 )

increased circulating alanine transaminase level ( J:369997 )

increased circulating alkaline phosphatase level ( J:369997 )

increased circulating aspartate transaminase level ( J:369997 )

abnormal complement protein level ( J:369997 )

• mice show deposition of C3 and C5b-9 (MAC) in glomeruli, both in the capillary wall and in the mesangium suggesting local complement activation and deposition in the kidneys

• livers show C3 deposition

increased complement C5 level ( J:369997 )

• mice show deposition of C5b-9 (MAC) in glomeruli, both in the capillary wall and in the mesangium

abnormal urine albumin level ( J:369997 )

• elevation in urinary albumin (normalized to urinary creatinine), indicting glomerular injury

hemoglobinuria ( J:369997 )

hematuria ( J:369997 )

• increase in urinary hemoglobin which suggests hematuria

immune system

abnormal complement protein level ( J:369997 )

• mice show deposition of C3 and C5b-9 (MAC) in glomeruli, both in the capillary wall and in the mesangium suggesting local complement activation and deposition in the kidneys

• livers show C3 deposition

increased complement C5 level ( J:369997 )

• mice show deposition of C5b-9 (MAC) in glomeruli, both in the capillary wall and in the mesangium

liver inflammation ( J:369997 )

• livers show inflammation in the portal region

hematopoietic system

decreased erythrocyte cell number ( J:369997 )

• slight, but significant, decrease in red blood cells

decreased hemoglobin content ( J:369997 )

• slight, but significant, decrease in total hemoglobin, but unaltered serum levels of free hemoglobin

• however, no change in hematocrit and mice do not present with classic signs of thrombotic microangiopathy and schistocytes are not seen

thrombocytosis ( J:369997 )

endocrine/exocrine glands