Activation of Multiple Signaling Pathways by Terminal Complement Complexes Involved in Myocellular Sodium Homeostasis

Abstract

Soluble C5b-9 complexes (SC5b-9), hemolytically inactive end-products of complement activation have long been considered to be irrelevant. Recent investigations, however, have demonstrated that SC5b-9 induces numerous biological effects via a series of intracellular signal transduction events. We have previously demonstrated that SC5b-9 enriched sera increased intracellular Na⁺ in rat skeletal muscles. This study was purposed to determine if the protein kinase C (PKC) or mitogen-activated protein kinase (MAPK) signaling pathway mediates the effects of SC5b-9. Fast-twitch extensor digitorum longus (EDL) muscles isolated from infant rats were incubated at 30°C for 60 minutes with 10% zymosan-activated rat sera (ZARS) as a source of complement. Heat-inactivated rat sera (HIRS) were used as a control. The muscles were also incubated with ZARS or HIRS in the presence of specific inhibitors against PKC (GF109203X) or MAPK (PD98059 and SB202190). Intracellular Na⁺ and K⁺ contents were then measured. ZARS significantly increased intracellular Na⁺ and the Na⁺/K⁺ ratio in EDL muscles as compared to HIRS. GF109203X, PD98059 and SB202190 markedly attenuated increase in myocellular Na⁺ induced by ZARS, respectively. We concluded that SC5b-9 enriched sera alter myocellular Na⁺ homeostasis, at least in part, via the mechanisms linked to PKC and MAPK signal transduction pathways.