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Critical role of Jun N-terminal Kinase and p38 in the pathogenesis of sepsis-induced down regulation of the renal outer medullary K+ channel-1 expression

Christoph Raspé1*, Patrick Kellner1,3*, Frederik Turner1, Michael Gekle2, Christoph Sauvant1 & Michael Bucher1
1 Department of Anesthesiology and Critical Care Medicine, Halle-Wittenberg University, Germany; 2 Department of Physiology, University of Halle-Wittenberg, Germany; 3 Department of Anesthesiology and Intensive Care Medicine, University of Lübeck, Germany   
* both authors have contributed equally to this work
[Applied Cardiopulmonary Pathophysiology 20: 3-19, 2016]


Objective: In sepsis, renal expression of the renal outer medullary K+ channel-1 (ROMK) is impaired via NFkB-induced cytokines. Mitogen activated protein kinases (MAPKs) are induced by lipopolysaccharide (LPS) or proinflammatory cytokines and ROMK-1 expression is downregulated via p38 or Jun N-terminal kinase (JNK).
We investigated how MAPK-inhibition of p38 or JNK affects ROMK-1 during sepsis.
Material and methods: Male C57/BL-6 mice (20–25 g) were used for in vivo and murine CCD cells (M1 cell line) for in vitro investigations. Mice were treated with LPS and MAPKs were inhibited by siRNA. M1 cells were stimulated with LPS or cytokines in addition to pathway inhibitors. In vivo, IL1β, TNFα and INFγ in blood were detected by cytometric bead immunoassay. In vitro, M1-cell line and a ROMK reporter gen assay were used.
Results: In vivo, LPS increased cytokines and decreased renal ROMK-1. Inhibition of JNK diminished LPS induction of cytokines and decrease of ROMK-1. JNK/p38 in kidney tissue were 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 cytokines decreased ROMK-1 expression. Inhibition of JNK/p38 had no effect on cytokine-induced down regulation of ROMK-1.
Conclusion: Inhibition of JNK decreases proinflammatory cytokines and increases renal ROMK1 in sepsis. The latter is not due to an effect on the renal level but likely on the level of macrophages.

Key words: cytokines, Jun N-terminal kinase, mitogen activated protein kinases, p38, renal outer medullary K+ channel-1, sepsis

Prof. Dr. Christoph Raspé,
D.E.S.A, E.D.I.C.
Department of Anesthesiology and Critical care medicine
Halle-Wittenberg University
Ernst-Grube-Straße 40
06120 Halle (Saale)

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