Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Bondeva T

PROVIDER: S-EPMC5800025 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

MORG1<sup>+/-</sup> mice are protected from histological renal damage and inflammation in a murine model of endotoxemia.

Bondeva Tzvetanka T Schindler Claudia C Schindler Katrin K Wolf Gunter G

BMC nephrology 20180205 1

<h4>Background</h4>The MAPK-organizer 1 (MORG1) play a scaffold function in the MAPK and/or the PHD3 signalling paths. Recently, we reported that MORG1<sup>+/-</sup> 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.<h4>Methods</h4>Endotoxemia was indu ...[more]

PMID: 29402223

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Project description:BackgroundLupus nephritis (LN) is an inflammatory disease of the kidneys affecting patients with systemic lupus erythematosus. Current immunosuppressive and cytotoxic therapies are associated with serious side effects and fail to protect 20-40% of LN patients from end-stage renal disease. In this study, we investigated whether a small heat shock protein, HSPB5, can reduce kidney inflammation and the clinical manifestations of the disease in NZB/W F1 mice. Furthermore, we investigated whether HSPB5 can enhance the effects of methylprednisolone, a standard-of-care drug in LN, in an endotoxemia mouse model.MethodsNZB/W F1 mice were treated with HSPB5, methylprednisolone, or vehicle from 23 to 38 weeks of age. Disease progression was evaluated by weekly proteinuria scores. At the end of the study, the blood, urine, spleens, and kidneys were collected for the assessment of proteinuria, blood urea nitrogen, kidney histology, serum IL-6 and anti-dsDNA levels, immune cell populations, and their phenotypes, as well as the transcript levels of proinflammatory chemokine/cytokines in the kidneys. HSPB5 was also evaluated in combination with methylprednisolone in a lipopolysaccharide-induced endotoxemia mouse model; serum IL-6 levels were measured at 24 h post-endotoxemia induction.ResultsHSPB5 significantly reduced terminal proteinuria and BUN and substantially improved kidney pathology. Similar trends, although to a lower extent, were observed with methylprednisolone treatment. Serum IL-6 levels and kidney expression of BAFF, IL-6, IFNγ, MCP-1 (CCL2), and KIM-1 were reduced, whereas nephrin expression was significantly preserved compared to vehicle-treated mice. Lastly, splenic Tregs and Bregs were significantly induced with HSPB5 treatment. HSPB5 in combination with methylprednisolone also significantly reduced serum IL-6 levels in endotoxemia mice.ConclusionsHSPB5 treatment reduces kidney inflammation and injury, providing therapeutic benefits in NZB/W F1 mice. Given that HSPB5 enhances the anti-inflammatory effects of methylprednisolone, there is a strong interest to develop HSBP5 as a therapeutic for the treatment of LN.

Project description:CONTEXT Slowly progressive chronic tubulo-interstitial damage jeopardizes long-term renal allograft survival. Both immune and non-immune mechanisms are thought to contribute, but the most promising targets for timely intervention have not been identified. OBJECTIVE In the current study we seek to determine the driving force behind progressive histological damage of renal allografts, without the interference of donor pathology, delayed graft function and acute graft rejection. DESIGN We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. PATIENTS Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection. RESULTS In this highly cross-validated study, we demonstrate the significant association of established, ongoing and future chronic histological damage with regulation of adaptive immune gene expression (T-cell and B-cell transcript sets) and innate immune response gene expression (dendritic cell, NK-cell, mast cell and granulocyte transcripts). We demonstrate the ability of gene expression analysis to perform as a quantitative marker for ongoing inflammation with a wide dynamic range: from subtle subhistological inflammation prior to development of chronic damage, over moderate subclinical inflammation associated with chronic histological damage, to marked inflammation of Banff-grade acute T-cell mediated rejection. CONCLUSION Progressive chronic histological damage after kidney transplantation is associated with significant regulation of both innate and adaptive immune responses, months before the histological lesions appear. This study therefore corroborates the hypothesis that quantitative inflammation below the diagnostic threshold of classic T-cell or antibody-mediated rejection is associated with early subclinical stages of progressive renal allograft damage. We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

MORG1<sup>+/-</sup> mice are protected from histological renal damage and inflammation in a murine model of endotoxemia.

Similar Datasets

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Tweets

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

MORG1<sup>+/-</sup> mice are protected from histological renal damage and inflammation in a murine model of endotoxemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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