| First Author | Bondeva T | Year | 2018 |
| Journal | BMC Nephrol | Volume | 19 |
| Issue | 1 | Pages | 29 |
| PubMed ID | 29402223 | Mgi Jnum | J:271862 |
| Mgi Id | MGI:6282238 | Doi | 10.1186/s12882-018-0826-4 |
| Citation | Bondeva T, et al. (2018) MORG1(+/-) mice are protected from histological renal damage and inflammation in a murine model of endotoxemia. BMC Nephrol 19(1):29 |
| abstractText | 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-alpha expression in MORG1 (+/+) mice. This was accompanied with enhanced infiltration of the inflammatory T-cells in renal tissue and activation of the NF-kappaB transcription factors. In contrast, endotoxemic MORG1 (+/-) showed significantly less tubular injury, reduced plasma IL-6 levels, significantly decreased renal TNF-alpha 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-2alpha in the kidneys of MORG1(+/-) mice than in wild-type mice, accompanied with a diminished phosphorylation of IkappaB-alpha and IKK alpha,beta and decreased iNOS mRNA in the renal tissues of the LPS-challenged MORG1(+/-) mice, indicating an inhibition of the NF-kappaB transcriptional activation. CONCLUSIONS: MORG1 heterozygosity protects against histological renal damage and shows anti-inflammatory effects in a murine endotoxemia model through modulation of HIF-2alpha stabilisation and/or simultaneous inhibition of the NF-kappaB signalling. Here, we show for the first time that MORG1 scaffold could represent the missing link between innate immunity and inflammation. |
