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Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada H3A 2B4
Submitted 12 March 2003 ; accepted in final form 21 June 2003
In the passive Heymann nephritis (PHN) model of rat membranous nephropathy,
complement C5b-9 causes sublytic injury of glomerular epithelial cells (GEC).
We previously showed that sublytic concentration of C5b-9 triggers a variety
of biological events in GEC. In the current study, we demonstrate that
complement activates p38 MAPK in GEC and address the role of p38 in
complement-mediated cell injury. When cultured rat GEC were stimulated with
complement, p38 kinase activity and phosphorylation were increased by
2.4-fold, compared with control. Treatment with p38 inhibitors
significantly augmented complement-mediated cytotoxicity. In contrast, when
the constitutively active mutant of transforming growth
factor-
-activated kinase 1 (TAK1), a kinase upstream of p38, was
expressed in GEC in an inducible manner, cytotoxicity was significantly
reduced, compared with uninduced cells. p38 inhibitors abolished the
protective effect of TAK1 expression. By analogy to cultured cells, p38
activity was also increased in glomeruli from rats with PHN and treatment with
the p38 inhibitor FR-167653 increased proteinuria. Complement induced
phosphorylation of MAPK-associated protein kinase-2 (MAPKAPK-2), a kinase
downstream of p38 in GEC. Heat shock protein (HSP27) is a
cytoskeleton-interacting substrate of MAPKAPK-2. Overexpression of the
wild-type HSP27, but not a non-phosphorylatable mutant, markedly reduced
complement-mediated GEC injury. In summary, complement activates p38 MAPK in
GEC in vitro and in glomeruli from rats with PHN. The activation of p38 MAPK
appears to be cytoprotective for GEC against complement-mediated GEC injury.
Phosphorylation of HSP27 may mediate this cytoprotection.
proteinuria; passive Heymann nephritis
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