Glomerulonephritis in mice with genetic deficiencies of the plasminogen system

A. R. Kitching, P. Carmeliet, V. Ploplis, D. Collen, E. Plow, Stephen R Holdsworth, P. Tipping

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Abstract

Glomerular fibrin deposition is an important mediator of injury in severe proliferative crescent glomerulonephritis (GN). The protective role of the fibrinolytic system in GN was studied using mice deficient in genes encoding plasminogen system components. In the accelerated autologous anti-glomerular basement membrane antibody model, acute GN was induced in mice deficient in u-PA (u-PA-/-; n=9), u-PA receptor (u-PAR-/- ; n=8), t-PA (t-PA-/-; n=5), combined t-PA and u-PA (t-PA-/-:u-PA-/-; n=5), plasminogen (Pig-/-; n=8), each compared to their own wild type (WT; n=20) mice. Renal injury was studied ten days after antibody injection. WT mice developed proliferative GN with fibrin deposition, occasional crescent formation and renal impairment. Plg-/- and combined t-PA-/-:u-PA-/- mice developed increased glomerular fibrin deposition compared to WT, necrosis of glomerular tufts, and higher percentages of crescent glomeruli (19±4% in Pig-/- vs 5±2% in WT; p=O.OI4 vs WT). Renal function, measured by serum creatinine (sCr) was significantly more impaired in Pig-/- mice (sCr 49+10 vs 14±3 umol/1 in WT; p=0.013), in u-PA-/mice (37±3 vs 26±4 umol/1 in WT; p<0.05) and in combined t-PA-/- :uPA-/- mice (36+8 vs 19+3 umol/1 in WT; p=0.03) but not in t-PA-/- mice (27+4 vs 26±5 umol/1 in WT; p=NS). The sCr of u-PAR-/-- mice (27+7 umol/1) was not different from WT. t-PA-/- mice (but not u-PA-/- or uPAR-/- mice) had increased glomerular hypercellularity (70±2 vs 60± 2 cells/glomerular cross section; p=0.006 vs WT) and increased glomerular PAS positive material (scored 0-3: 1.2+0.2 vs 0.7510.05; p=0.02) compared to WT. Thus, induction of GN in Pig-/- or t-PAv:uPA-/- mice results in severe disease, whereas mice deficient in u-PA or tPA (but not u-PAR) have some evidence of increased disease severity. These results indicate that the fibrinolytic system plays a significant role in maintaining glomerular function in proliferative forms of GN.

Original languageEnglish
Number of pages1
JournalFibrinolysis
Volume10
Issue numberSUPPL. 3
Publication statusPublished - 1 Dec 1996

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