Center for Molecular Medicine Cologne

Roman-Ulrich Müller - 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.

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.

Project Related Publications

  1. Johnsen, M., Kubacki, T., Yeroslaviz, A., Späth, M.R., Mörsdorf, J., Göbel, H., Bohl, K., Ignarski, M., Meharg, C., Habermann, B., Altmüller, J., Beyer, A., Benzing, T., Schermer, B., Burst, V., Müller, R.-U. The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury. J. Am. Soc. Nephrol.31 (2020), 716–730. doi.org/10.1681/ASN.2019050534
  2. Esmaillie, R., Ignarski, M., Bohl, K., Krüger, T., Ahmad, D., Seufert, L., Schermer, B., Benzing, T., Müller, R.-U.*, Fabretti, F. Activation of hypoxia-inducible factor signaling modulates the RNA protein interactome in Caenorhabditis elegans. iScience 2019. * corresponding authorshipdoi.org/10.1016/j.isci.2019.11.039, highlighted in the “most read” section of iScience December 2019
  3. M. Ignarski, C. Rill, R.W.J. Kaiser, M. Kaldirim, R. Neuhaus, R. Esmaillie, X. Li, C. Klein, K. Bohl, M. Petersen, C.K. Frese, M. Höhne, I. Atanassov, M.M. Rinschen, K. Höpker, B. Schermer, T. Benzing, C. Dieterich, F. Fabretti, R.-U. Müller, The RNA-Protein Interactome of Differentiated Kidney Tubular Epithelial Cells, J. Am. Soc. Nephrol. 30 (2019) 564–576. doi:10.1681/ASN.2018090914. rated among “this month’s highlights”
  4. Späth, M.R., Bartram, M.P., Palacio-Escat, N., Hoyer, K.J.R., Debes, C., Demir, F., Schroeter, C.B., Mandel, A.M., Grundmann, F., Ciarimboli, G., Beyer, A., Kizhakkedathu, J.N., Brodesser, S., Göbel, H., Becker, J.U., Benzing, T., Schermer, B., Höhne, M., Burst, V., Saez-Rodriguez, J., Huesgen, P.F., Müller, R.-U.*, Rinschen, M.M.*, 2019. The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury. Kidney International (2018) 95, 333–349. doi.org/10.1016/j.kint.2018.08.037*shared corresponding/senior authorship
  5. Grundmann, F., Müller, R.-U., Reppenhorst, A., Hülswitt, L., Späth, M.R., Kubacki, T., Scherner, M., Faust, M., Becker, I., Wahlers, T., Schermer, B., Benzing, T. and Burst, V. Preoperative Short-Term Calorie Restriction for Prevention of Acute Kidney Injury After Cardiac Surgery: A Randomized, Controlled, Open-Label, Pilot Trial. J Am Heart Assoc 7. (2018), https://doi.org/10.1161/JAHA.117.008181
  6. M.P. Bartram, T. Mishra, N. Reintjes, F. Fabretti, H. Gharbi, A.C. Adam, H. Göbel, M. Franke, B. Schermer, S. Haneder, T. Benzing, B.B. Beck and R.-U. Müller, Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer, BMC Med. Genet. 18 (2017) 53. doi:10.1186/s12881-017-0416-5.
  7. H. Gharbi, F. Fabretti, P. Bharill, M.M. Rinschen, S. Brinkkötter, P. Frommolt, V. Burst, B. Schermer, T. Benzing and R.-U. Müller, Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner, Aging Cell (2013). doi:10.1111/acel.12081.
  8. R.-U. Müller, F. Fabretti, S. Zank, V. Burst, T. Benzing and B. Schermer, The von Hippel Lindau tumor suppressor limits longevity, J. Am. Soc. Nephrol. 20 (2009) 2513–2517. doi:10.1681/ASN.2009050497.
Prof. Dr. Roman-Ulrich Müller CMMC Cologne
Prof. Dr. Roman-Ulrich Müller

Clinic II of Internal Medicine / RG location - CECAD Building

CMMC - assoc. Research Group

+49 221 478 89033

+49 221 478 89041

Clinic II of Internal Medicine / RG location - CECAD Building

Kerpener Str. 62

50937 Cologne

http://www.kidneyresearchcenter.org/51/Research/Renal-Damage-and-Cancer/RNA-biology-in-renal-damage-and-cancer-%E2%80%93-Roman-Ulrich-Mueller.htm

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Roman-Ulrich Müller

Link to PubMed

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Group Members

Katrin Bohl
Reza Esmaillie
Samantha Filipow
Serena Greco-Torres
Michael Ignarski
Lisa Seufert