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

Abstract

BackgroundThe 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.MethodsEndotoxemia 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.ResultsLPS 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.ConclusionsMORG1 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.Electronic supplementary materialThe online version of this article (10.1186/s12882-018-0826-4) contains supplementary material, which is available to authorized users.

Ramipril pretreatment worsened renal injury and survival despite a reduction in renal inflammation in experimentally induced sepsis in mice

“…Furthermore, we also tested the influence of ramipril on sepsis-induced T-cell infiltration in renal tissue, using immunological detection of CD3 + T lymphocytes. In agreement with our previous observation, 11 sepsis induced a massive accumulation of interstitial T cells in renal tissue ( Figure 5(c) , CLP panel), whereas ramipril pre-treatment before sepsis induction significantly improved renal inflammation as detected by fewer CD3 + T cells in kidney sections ( Figure 5(c) , ramipril panel and Figure 5(d) ) compared with sepsis alone ( Figure 5(c) , ramipril panel).…”

“…We recently reported that HIF-2α, but not HIF-1α, protein expression was significantly increased in endotoxemic mice. 11 Therefore, we examined whether ramipril pretreatment may affect HIF-2α expression in renal tissue under basal and septic conditions. Immunohistochemistry studies revealed that, in agreement with our previous observation, the protein expression of HIF-2α was significantly elevated in CLP mice compared with the control SOP mice were increased in CLP and ramipril + CLP group respectively to the corresponding SOP control group.…”

Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10

“…Therefore, KIM-1 and NGAL were measured, which are biomarkers for early diagnosis of AKI, and increased upon damage to the normal kidney morphology, especially tubular injury involving the proximal tubular epithelial cells ( Vaidya et al, 2008 ; Simsek et al, 2013 ; Luo et al, 2016 ). The level of these markers were significantly high in the kidney of 24-h LPS treated animals, which is consistent with other studies ( Bondeva et al, 2018 ; Kim et al, 2020 ). C21 reduced the LPS-driven increase in KIM-1 and NGAL in the kidney homogenates, although these changes were not very dramatic, but still statistically significant as compared to LPS.…”

Lipopolysaccharide-based endotoxemia produce toxicity in peripheral organs and microglia migration in a dose-dependent manner in rat substantia nigra

“…Although we show basal levels in vehicle and C(+) groups, our data show that, regardless of the dose, no presence of inflammatory process exists 8 days after LPS administration. On the other hand, the histological alterations observed in the organs studied suggest sepsis-type physiological alterations such as intraparenchymal damage in the lungs, heart, liver, spleen and kidney [5,6]. In hepatic parenchyma, we found mild hepatic necrosis, increase in the size of the sinusoidal space and vasodilation, as was reported by Abdel-Salam et al [1].…”