Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models

Schindler, Katrin; Bondeva, Tzvetanka; Schindler, Claudia; Claus, Ralf A.; Franke, Sybille; Wolf, Günter

doi:10.1093/ndt/gfv442

Cited by 14 publications

(18 citation statements)

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“…Yet, during hypoxia the enzymatic activity of PHDs is suppressed due to low oxygen levels leading to subsequent stabilisation and activation of HIFs [ 13 ]. There is a growing body of research demonstrating the beneficial effects of pharmacological HIF activation [ 7 , 8 , 33 – 35 ] or administration of the proteins which are generated due to HIF target gene expression such as EPO [ 9 , 36 ] and VEGF. Yet, studies have consistently shown the complexity in determining the most optimal timing for application of HIF inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that LPS can activate the hypoxia-inducible transcription factor-1 alpha (HIF-1α) under normoxic conditions [ 5 ]. The pharmacological activation of HIF-1α through inhibition of HIF-prolyl-hydroxylases (PHDs) [ 6 ] or administration of erythropoietin, a HIFs target gene, improved renal function and reduced acute kidney injury in endotoxemic mice [ 7 ] as well as in mice suffering from polymicrobial sepsis [ 8 ]. Recently, we reported that preconditional suppression of PHDs by application of 3,4-dihydroxybezoate (3,4-DHB), a non-specific PHDs inhibitor, was renoprotective in two murine septic models [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

Bondeva

Schindler

et al. 2018

BMC Nephrol

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bondeva

Schindler

et al. 2018

BMC Nephrol

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“…reported increased mortality in a sepsis model of kidney injury, possibly contributed to by off-target effects of the prolyl hydroxylase inhibitors used. 32 Importantly, the fact that C1q secretion and HIF inactivation utilize structurally related oxygenases, which have different substrate selectivities and active sites, suggests that the development of PHD inhibitors that selectively activate HIF without compromising C1q secretion is possible.…”

Section: Discussionmentioning

confidence: 99%

Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase and is sensitive to off-target inhibition by prolyl hydroxylase domain inhibitors that stabilize hypoxia-inducible factor

Kiriakidis

Hoer

Burrows

et al. 2017

Kidney International

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Complement C1q is part of the C1 macromolecular complex that mediates the classical complement activation pathway: a major arm of innate immune defense. C1q is composed of A, B, and C chains that require post-translational prolyl 4-hydroxylation of their N-terminal collagen-like domain to enable the formation of the functional triple helical multimers. The prolyl 4-hydroxylase(s) that hydroxylate C1q have not previously been identified. Recognized prolyl 4-hydroxylases include collagen prolyl-4-hydroxylases (CP4H) and the more recently described prolyl hydroxylase domain (PHD) enzymes that act as oxygen sensors regulating hypoxia-inducible factor (HIF). We show that several small-molecule prolyl hydroxylase inhibitors that activate HIF also potently suppress C1q secretion by human macrophages. However, reducing oxygenation to a level that activates HIF does not compromise C1q hydroxylation. In vitro studies showed that a C1q A chain peptide is not a substrate for PHD2 but is a substrate for CP4H1. Circulating levels of C1q did not differ between wild-type mice or mice with genetic deficits in PHD enzymes, but were reduced by prolyl hydroxylase inhibitors. Thus, C1q is hydroxylated by CP4H, but not the structurally related PHD hydroxylases. Hence, reduction of C1q levels may be an important off-target side effect of small molecule PHD inhibitors developed as treatments for renal anemia.

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“…Conversely, mice treated with DMOG could not be protected against polymicrobial sepsis, due to suppressing the inflammatory response followed by an overwhelming infection . Pretreatment of mice with another PHD inhibitor, 3,4‐dihydroxybenzoate (3,4‐DHB), improves renal function after cecal ligation and puncture (CLP); however, the PHD inhibition leads to an increased mortality rate due to liver dysfunction with massive glycogen loss and apoptosis of hepatocytes . Treatment with Edaravone, a potent radical scavenger, suppresses oxidative stress and protects against septic myocardial injury and dysfunction by HIF1α activation and subsequent heme oxygenase 1 induction .…”

Section: Crosstalk Between Hif and Sepsismentioning

confidence: 99%

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

2020

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Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced host response to infection. Despite huge investments, sepsis remains a contemporary threat with significant burden on health systems. Vascular dysfunction and elevated oxygen consumption by highly metabolically active immune cells result in tissue hypoxia during inflammation. The transcription factor hypoxia-inducible factor-1a (HIF1a), and its family members, plays an important role in cellular metabolism and adaptation to cellular stress caused by hypoxia. In this review, we discuss the role of HIF in sepsis. We show possible mechanisms by which the inflammatory response activated during sepsis affects the HIF pathway. The activated HIF pathway in turn changes the metabolism of both innate and adaptive immune cells. As HIF expression in leukocytes of septic patients can be directly linked with mortality, we discuss multiple ways of interfering with the HIF signaling pathway.

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Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models

Abstract: In summary, the pharmacological activation of HIFs by 3,4-DHB administration, although it showed renoprotective effects in sepsis-related kidney injury, induced more severe problems in other organs such as the liver during sepsis, leading to increased mortality.

Cited by 14 publications

References 60 publications

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

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

Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase and is sensitive to off-target inhibition by prolyl hydroxylase domain inhibitors that stabilize hypoxia-inducible factor

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

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