In sepsis the renal expression of ROMK1 is impaired via NF?B induced cytokines (IL1β, TNFα and INFγ). Mitogen activated protein kinases (MAPKs) p38 or JNK are induced by LPS or pro-inflammatory cytokines and ROMK1 expression is down regulated by p38 or JNK. We investigated how MAPK inhibition affects ROMK1 expression in LPS induced sepsis and in cell culture.

Mice were treated with LPS (10mg/kg), MAPKs were inhibited by siRNA and measurements were made after 24h. Cytokines were detected by cytometric bead immunoassay. In vitro, a mouse collecting duct cell line (M1) and a ROMK reporter gen assay were used. IL1β, TNFα and INFγ were applied and MAPKs were inhibited.

In vivo, LPS increased IL1β, TNFα and INFγ and decreased renal ROMK1. Inhibition of MAPKs diminished LPS induction of cytokines and the decrease of ROMK1. JNK or p38 in kidney tissue was not changed after LPS nor affected by either MAPK inhibition, indicating that the regulation observed is due to cytokine release in circulating macrophages. Incubation of M1 cells with IL1β, TNFα and INFγ, decreased ROMK1 expression. Inhibition of JNK, p38 (or ERK1/2) had no effect on cytokine induced down regulation of ROMK1 expression.

(i) Inhibition of JNK or p38 decreases pro-inflammatory cytokines and increases renal ROMK1 in sepsis. (ii) The latter is not due to an effect on the renal level but likely on the level of macrophages. (iii) The cellular signaling of cytokine induced regulation of ROMK1 has to be further investigated.

Supported by DFG Grant SCH 264/2-1.