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Müller, Roman-Ulrich - assoc. RG 13

Hypoxia-signaling at the crossroads of cellular stress resistance and tumorigenesis

Abstract

The cellular response to a lack of oxygen is largely dependent on the activation of hypoxia-inducible transcription factors (HIF). Upon hypoxia, stabilization of these factors and execution of their transcriptional program induces a metabolic adaptation to low oxygen levels, which is required for organ physiology.
This programme is of special importance in the kidney taking into account the low intra-parenchymal oxygen pressure in combination with energy-demanding transport processes in renal epithelial cells. Consequently, it is not surprising that an activation of hypoxia signalling can also protect from acute kidney injury by increasing cellular stress resistance.
The concept of hypoxic preconditioning can be mediated either by direct pharmacological activation of HIF or exposure to low oxygen pressure and is actively studied as a novel tool to prevent acute kidney injury in the clinical setting. However, induction of HIF-signaling is also the key process underlying the pathogenesis of renal cell carcinoma indicating that stress resistance and tumorigenesis are closely related cellular states.
In this project, we combine models of hypoxic preconditioning in mouse and nematode with genetic models of multitumor syndromes associated with renal cell carcinoma (e.g. Von-Hippel-Lindau syndrome, Birt-Hogg-Dube syndrome) to elucidate the mechanistic role of hypoxia signalling. Using these models in combination with state-of-the-art molecular biology we focus on the mechanistic role of RNA-protein interactions involved in cellular stress resistance.

Figure 1
Fig. 1 Preconditioning strategies to protect from acute kidney injury The activation of cellular stress resistance mechanisms by preconditioning is one of the most promising approaches for the protection from acute kidney injury. Here, dietary regimens and interventions activating hypoxia signaling are among the best studied strategies. Image derived from Späth et al. F1000Research 2020, 9(F1000 Faculty Rev):237

Clinical and Medical Relevance

Acute kidney injury (AKI) is one of the most frequent complications in hospitalized patients and its incidence is rising alongside the demographic changes of our society. AKI is strongly associated with worse clinical outcome including mortality and chronic kidney disease. Despite the clear clinical importance, there are no measures available to treat or prevent AKI in a targeted fashion. A detailed understanding of pathways mediating renal organ protection is urgently required to develop novel approaches to prevent AKI and its consequences.

Figure 2
Fig. 2 Automated lifespan analysis of C. elegans mutants. Nematode lifespan is an optimal surrogate parameter to screen for interventions that increase stress resistance. Consequently, we use this model in our search for organ protective measures. Here, we established a Lifespan machine that allows for the automated analysis of large numbers exposed to different interventions. A. Image of the lifespan machine consisting of scanners connected to a laptop running the required software. B. Upper panel: Lifespan analysis of wild-type worms. Middle panel: Lifespan analysis of wild-type (red) and vhl-1(ok161) mutant worms (yellow). Mutation of vhl-1 leads to an induction of HIF-Signaling. C. Lifespan analysis of wild-type (red) and daf-2(e1370) (blue). DAF-2 is the nematode insulin receptor. Inhibition of insulin-signalling is one of the best-studied interventions leading to longevity. Graphs provided by Reza Esmaillie.
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  • Seufert L, Benzing T, Ignarski M, and Muller RU (2022). RNA-binding proteins and their role in kidney disease. Nat Rev Nephrol18, 153-170. doi:10.1038/s41581-021-00497-1.
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  • Seufert L, Benzing T, Ignarski M, and Muller RU (2021). RNA-binding proteins and their role in kidney disease. Nat Rev Nephrol. doi:10.1038/s41581-021-00497-1.
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  • Spath MR, Koehler FC, Hoyer-Allo KJR, Grundmann F, Burst V, and Muller RU (2020). Preconditioning strategies to prevent acute kidney injury. F1000Res9. doi:10.12688/f1000research.21406.1.
Prof. Dr. Roman-Ulrich Müller CMMC Cologne
Prof. Dr. Roman-Ulrich Müller

Clinic II of Internal Medicine

CMMC - PI - assoc. RG 13

Curriculum Vitae - Roman-Ulrich Müller
Publications - Roman-Ulrich Müller

Link to PubMed

Group Members

Sita Arjune
Katrin Bohl
Reza Esmaillie
Samantha Filipow
Serena Greco-Torres
Johanna Hoyer-Allo
Michael Ignarski
Felix Köhler
Francisco Lopes
Pedro Rojas Morales
Willian Salgueiro
Lisa Seufert
Martin Späth


 

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University of Cologne (Universtität zu Köln)
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