Untersuchungen zu der Rolle von MORG1 und HIF-1α in der Sepsis induzierten Nierenschädigung
Sepsis is a generalized hyperinflammatoric host response caused by infection. Renal dysfunction is frequently associated with sepsis due to limited supply of tissue oxygen in renal tissue, and extremely strong host immune response. Hypoxia inducible factor–1 and 2 alpha (HIF–1/2α) are essential for cellular adaptation to hypoxic conditions. Under normoxia, the regulation of HIF–1α occurs by prolylhydroxylases (PHDs) via proteasomal degradation. The scaffold protein MAPK organizer 1 (MORG1) interacts with PHD3 and provides the regulation and stabilization of HIF–1/2α proteins. The role of MORG1 in relation to enhanced HIF–1α protein levels in sepsis–induced renal injury has not yet been investigated. Therefore, in this study we have analysed the influence of sepsis dependent kidney damage in Morg1+/- and wild–type mice. Peritonitis was induced in cecal ligation and punction (CLP) and peritoneal contamination and infection (PCI), in addition endotoxemia was studied in lipopolysaccharides (LPS) treated mice. To figure out impact of MORG1–PHD3–HIF complex in sepsis–induced renal injury kidney morphology, function, and inflammatory markers were explored as well as survival studies were performed. HIF–1/2α was accumulated in renal tissue after sepsis induction. The reduction of MORG1 or/and stabilization of HIF–1/2α protein showed renoprotective effects in kidney of Morg1+/- animals, demonstrated as less vacuolization, tubular apoptosis, and necrosis after sepsis or LPS. In agreement with these observations, Morg1+/- mice were protected against infiltration of CD3+–T–cells. However, that did not reflect systemic inflammation, as we did not detect significant differences in inflammatory cytokine concentrations in blood plasma. Furthermore, renal function was deteriorated due to sepsis and endotoxemia in both genotypes to similar extend. Furthermore, our survival data have shown that suppression of MORG1 expression was correlated with increased lethality of septic animals.