Center for Molecular Medicine Cologne

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.

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.

  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.
  • Hoyer-Allo KJR, Spath MR, Brodesser S, Zhu Y, Binz-Lotter J, Hohne M, Broenneke H, Bohl K, Johnsen M, Kubacki T, Kiefer K, Seufert L, Koehler FC, Grundmann F, Hackl MJ, Schermer B, Bruning J, Benzing T, Burst V, and Muller RU (2022). Caloric restriction reduces the pro-inflammatory eicosanoid 20-hydroxyeicosatetraenoic acid to protect from acute kidney injury. Kidney Int. doi:10.1016/j.kint.2022.04.033.
  • Koehler FC, Fu CY, Spath MR, Hoyer-Allo KJR, Bohl K, Gobel H, Lackmann JW, Grundmann F, Osterholt T, Gloistein C, Steiner JD, Antebi A, Benzing T, Schermer B, Schwarz G, Burst V, and Muller RU (2022). A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism. Transl Res244, 32-46. doi:10.1016/j.trsl.2022.02.003.
  • Unnersjo-Jess D, Ramdedovic A, Hohne M, Butt L, Koehler FC, Muller RU, Hoyer PF, Blom H, Schermer B, and Benzing T (2022). Three-Dimensional Super-Resolved Imaging of Paraffin-Embedded Kidney Samples. Kidney3603, 446-454. doi:10.34067/KID.0005882021.
  • Aapkes SE, Bernts LHP, van den Berg AP, van den Berg M, Blokzijl H, Cantineau AEP, van Gastel MDA, de Haas RJ, Kappert P, Muller RU, Nevens F, Torra R, Visser A, Drenth JPH, and Gansevoort RT (2022). Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study. BMC Gastroenterol22, 82. doi:10.1186/s12876-022-02142-y.
  • Koehler FC, Di Cristanziano V, Spath MR, Hoyer-Allo KJR, Wanken M, Muller RU, and Burst V (2022). The kidney in hantavirus infection-epidemiology, virology, pathophysiology, clinical presentation, diagnosis and management. Clin Kidney J15, 1231-1252. doi:10.1093/ckj/sfac008.
  • Koehler FC, Spath MR, Hoyer-Allo KJR, and Muller RU (2022). Mechanisms of Caloric Restriction-Mediated Stress-Resistance in Acute Kidney Injury. Nephron146, 234-238. doi:10.1159/000517733.
  • 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.
  • Muller RU, Messchendorp AL, Birn H, Capasso G, Cornec-Le Gall E, Devuyst O, van Eerde A, Guirchoun P, Harris T, Hoorn EJ, Knoers N, Korst U, Mekahli D, Le Meur Y, Nijenhuis T, Ong ACM, Sayer JA, Schaefer F, Servais A, Tesar V, Torra R, Walsh SB, and Gansevoort RT (2022). An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International. Nephrol Dial Transplant37, 825-839. doi:10.1093/ndt/gfab312.
  • Strubl S, Oehm S, Torres JA, Grundmann F, Haratani J, Decker M, Vuong S, Kaur Bhandal A, Methot N, Haynie-Cion R, Meyer F, Siedek F, Korst U, Muller RU, and Weimbs T (2022). Ketogenic dietary interventions in autosomal dominant polycystic kidney disease-a retrospective case series study: first insights into feasibility, safety and effects. Clin Kidney J15, 1079-1092. doi:10.1093/ckj/sfab162.
  • Eberhardt KA, Dewald F, Heger E, Gieselmann L, Vanshylla K, Wirtz M, Kleipass F, Johannis W, Schommers P, Gruell H, Brensing KA, Muller RU, Augustin M, Lehmann C, Koch M, Klein F, and Di Cristanziano V (2021). Evaluation of a New Spike (S)-Protein-Based Commercial Immunoassay for the Detection of Anti-SARS-CoV-2 IgG. Microorganisms9. doi:10.3390/microorganisms9040733.
  • Hoyer-Allo KJR, Spath MR, Hanssen R, Johnsen M, Brodesser S, Kaufmann K, Kiefer K, Koehler FC, Gobel H, Kubacki T, Grundmann F, Schermer B,Bruning J, Benzing T, Burst V, and Muller RU (2021). Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury. Int J Mol Sci22. doi:10.3390/ijms22115485.
                                                                • Koehler FC, Blomberg L, Brehm TT, Buttner S, Cornely OA, Degen O, Di Cristanziano V, Dolff S, Eberwein L, Hoxha E, Hoyer-Allo KJR, Rudolf S, Spath MR, Wanken M, Muller RU, and Burst V (2021). Development and design of the Hantavirus registry - HantaReg - for epidemiological studies, outbreaks and clinical studies on hantavirus disease. Clin Kidney J14, 2365-2370. doi:10.1093/ckj/sfab053.
                                                                • Koehler FC, Spath MR, Hoyer-Allo KJR, and Muller RU (2021). Mechanisms of Caloric Restriction-Mediated Stress-Resistance in Acute Kidney Injury. Nephron, 1-5. doi:10.1159/000517733.

                                                                • 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.
                                                                                                                                                                                                                                                                                  • Talyan S, Filipow S, Ignarski M, Smieszek M, Chen H, Kuhne L, Butt L, Gobel H, Hoyer-Allo KJR, Koehler FC, Altmuller J, Brinkkotter P, Schermer B, Benzing T, Kann M, Muller RU, and Dieterich C (2021). CALINCA-A Novel Pipeline for the Identification of lncRNAs in Podocyte Disease. Cells10. doi:10.3390/cells10030692.
                                                                                                                                                                                                                                                                                  • Braun F, Rinschen M, Buchner D, Bohl K, Plagmann I, Bachurski D, Richard Spath M, Antczak P, Gobel H, Klein C, Lackmann JW, Kretz O, Puelles VG, Wahba R, Hallek M, Schermer B, Benzing T, Huber TB, Beyer A, Stippel D, Kurschat CE, and Muller RU (2020). The proteomic landscape of small urinary extracellular vesicles during kidney transplantation. J Extracell Vesicles10, e12026. doi:10.1002/jev2.12026.
                                                                                                                                                                                                                                                                                                                                    • Grundmann F, Muller RU, Hoyer-Allo KJR, Spath MR, Passmann E, Becker I, Pfister R, Baldus S, Benzing T, and Burst V (2020). Dietary restriction for prevention of contrast-induced acute kidney injury in patients undergoing percutaneous coronary angiography: a randomized controlled trial. Sci Rep10, 5202. doi:10.1038/s41598-020-61895-2.
                                                                                                                                                                                                                                                                                                                                                                                • Johnsen M, Kubacki T, Yeroslaviz A, Spath MR, Morsdorf J, Gobel H, Bohl K, Ignarski M, Meharg C, Habermann B, Altmuller J, Beyer A, Benzing T, Schermer B, Burst V, and Muller RU (2020). The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury. J Am Soc Nephrol31, 716-730. doi:10.1681/ASN.2019050534.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        • Schermer B, Fabretti F, Damagnez M, Di Cristanziano V, Heger E, Arjune S, Tanner NA, Imhof T, Koch M, Ladha A, Joung J, Gootenberg JS, Abudayyeh OO, Burst V, Zhang F, Klein F, Benzing T, and Muller RU (2020). Rapid SARS-CoV-2 testing in primary material based on a novel multiplex RT-LAMP assay. PLoS One15, e0238612. doi:10.1371/journal.pone.0238612.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Siedek F, Grundmann F, Weiss K, Pinto Dos Santos D, Arjune S, Haneder S, Persigehl T, Muller RU, and Baessler B (2020). Magnetic Resonance Kidney Parenchyma-T2 as a Novel Imaging Biomarker for Autosomal Dominant Polycystic Kidney Disease. Invest Radiol55, 217-225. doi:10.1097/RLI.0000000000000633.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    • Muller RU, and Schermer B (2020). Hippo signaling-a central player in cystic kidney disease? Pediatr Nephrol35, 1143-1152. doi:10.1007/s00467-019-04299-3.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                • 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

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                Publications - Roman-Ulrich Müller

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                Group Members

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