Journal Article

MORG1+/− mice are protected from histological renal damage and inflammation in a murine model of endotoxemia

Bondeva, Tzvetanka, Schindler, Claudia, Schindler, Katrin, Wolf, Gunter

2018

Overview

Background The MAPK-organizer 1 (MORG1) play a scaffold function in the MAPK and/or the PHD3 signalling paths. Recently, we reported that MORG1 +/− mice are protected from renal injury induced by systemic hypoxia and acute renal ischemia-reperfusion injury via increased hypoxia-inducible factors (HIFs). Here, we explore whether MORG1 heterozygosity could attenuate renal injury in a murine model of lipopolysaccharide (LPS) induced endotoxemia. Methods Endotoxemia was induced in mice by an intraperitoneal (i.p) application of 5 mg/kg BW LPS. The renal damage was estimated by periodic acid Schiff’s staining; renal injury was evaluated by detection of urinary and plasma levels of neutrophil gelatinase-associated lipocalin and albumin/creatinine ratio via ELISAs. Renal mRNA expression was assessed by real-time PCR, whereas the protein expression was determined by immunohistochemistry or Western blotting. Results LPS administration increased tubular injury, microalbuminuria, IL-6 plasma levels and renal TNF-α expression in MORG1 +/+ mice. This was accompanied with enhanced infiltration of the inflammatory T-cells in renal tissue and activation of the NF-κB transcription factors. In contrast, endotoxemic MORG1 +/− showed significantly less tubular injury, reduced plasma IL-6 levels, significantly decreased renal TNF-α expression and T-cells infiltration. In support, the renal levels of activated caspase-3 were lower in endotoxemic MORG1 +/− mice compared with endotoxemic MORG1 +/+ mice. Interestingly, LPS application induced a significantly higher accumulation of renal HIF-2α in the kidneys of MORG1 +/− mice than in wild-type mice, accompanied with a diminished phosphorylation of IκB-α and IKK α,β and decreased iNOS mRNA in the renal tissues of the LPS-challenged MORG1 +/− mice, indicating an inhibition of the NF-κB transcriptional activation. Conclusions MORG1 heterozygosity protects against histological renal damage and shows anti-inflammatory effects in a murine endotoxemia model through modulation of HIF-2α stabilisation and/or simultaneous inhibition of the NF-κB signalling. Here, we show for the first time that MORG1 scaffold could represent the missing link between innate immunity and inflammation.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Acute Kidney Injury - genetics / Acute Kidney Injury - pathology / Acute Kidney Injury - prevention & control / Acute renal failure / Adaptor Proteins, Signal Transducing - genetics / Animals / Anti-inflammatory drugs / Care and treatment / Cell Biology and Transport Physiology / Disease Models, Animal / Dosage and administration / Endotoxemia / Endotoxemia - genetics / Endotoxemia - pathology / Health aspects / HIF-2α / Inflammation / Inflammation - genetics / Inflammation - pathology / Internal Medicine / Lipopolysaccharides / Male / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Mice, Transgenic / MORG1 / Nephrology / PHD3 / Random Allocation / Renal injury / Research Article