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.
  • 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.
     
  • 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.
  • 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. https://doi.org/10.1681/ASN.2019050534
  • 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”
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • Abo Zed SED, Hackl A, Bohl K, Ebert L, Kieckhofer E, Muller C, Becker K, Fink G, Nusken KD, Nusken E, Muller RU, Schermer B, and Weber LT (2023). Mycophenolic acid directly protects podocytes by preserving the actin cytoskeleton and increasing cell survival. Sci Rep 13, 4281. doi:10.1038/s41598-023-31326-z.
     
  • Arjune S, Grundmann F, Todorova P, Hendrix C, Pfister R, Ten Freyhaus H, and Muller RU (2023). Cardiac Manifestations in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD): A Single-Center Study. Kidney 360 4, 150-161. doi:10.34067/KID.0002942022.
     
  • Arjune S, Oehm S, Todorova P, Gansevoort RT, Bakker SJL, Erger F, Benzing T, Burst V, Grundmann F, Antczak P, and Muller RU (2023). Copeptin in autosomal dominant polycystic kidney disease: real-world experiences from a large prospective cohort study. Clin Kidney J 16, 2194-2204. doi:10.1093/ckj/sfad118.
     
  • Arjune S, Spath MR, Oehm S, Todorova P, Schunk SJ, Lettenmeier K, Chon SH, Bartram MP, Antczak P, Grundmann F, Fliser D, and Muller RU (2024). DKK3 as a potential novel biomarker in patients with autosomal polycystic kidney disease. Clin Kidney J 17, sfad262. doi:10.1093/ckj/sfad262.
     
  • Cukoski S, Lindemann CH, Arjune S, Todorova P, Brecht T, Kuhn A, Oehm S, Strubl S, Becker I, Kammerer U, Torres JA, Meyer F, Schomig T, Hokamp NG, Siedek F, Gottschalk I, Benzing T, Schmidt J, Antczak P, Weimbs T, Grundmann F, and Muller RU (2023). Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD-a randomized controlled trial. Cell Rep Med 4, 101283. doi:10.1016/j.xcrm.2023.101283.
     
  • Fuchs A, Dederichs J, Arjune S, Todorova P, Wostmann F, Antczak P, Illerhaus A, Gathof B, Grundmann F, Muller RU, and Annecke T (2023). Microvascular perfusion, perfused boundary region and glycocalyx shedding in patients with autosomal dominant polycystic kidney disease: results from the GlycoScore III study. Clin Kidney J 16, 384-393. doi:10.1093/ckj/sfac229.
     
  • Karner LA, Arjune S, Todorova P, Maintz D, Grundmann F, Persigehl T, and Müller RU (2023). Cyst Fraction as a Biomarker in Autosomal Dominant Polycystic Kidney Disease. Journal of Clinical Medicine 12. doi:Artn 32610.3390/Jcm12010326.
     
  • Oehm S, Steinke K, Schmidt J, Arjune S, Todorova P, Heinrich Lindemann C, Wostmann F, Meyer F, Siedek F, Weimbs T, Muller RU, and Grundmann F (2023). RESET-PKD: a pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 38, 1623-1635. doi:10.1093/ndt/gfac311.
     
  • Ripa R, Ballhysa E, Steiner JD, Laboy R, Annibal A, Hochhard N, Latza C, Dolfi L, Calabrese C, Meyer AM, Polidori MC, Muller RU, and Antebi A (2023). Refeeding-associated AMPK(gamma1) complex activity is a hallmark of health and longevity. Nat Aging 3, 1544-1560. doi:10.1038/s43587-023-00521-y.
     
  • Salgueiro WG, Soares MV, Martins CF, Paula FR, Rios-Anjos RM, Carrazoni T, Mori MA, Muller RU, Aschner M, Dal Belo CA, and Avila DS (2023). Dopaminergic modulation by quercetin: In silico and in vivo evidence using Caenorhabditis elegans as a model. Chem Biol Interact 382, 110610. doi:10.1016/j.cbi.2023.110610.
     
  • Selle J, Bohl K, Hopker K, Wilke R, Dinger K, Kasper P, Abend B, Schermer B, Muller RU, Kurschat C, Nusken KD, Nusken E, Meyer D, Savai Pullamsetti S, Schumacher B, Dotsch J, and Alcazar MAA (2023). Perinatal Obesity Sensitizes for Premature Kidney Aging Signaling. Int J Mol Sci 24. doi:10.3390/ijms24032508.
     
  • Spath MR, Hoyer-Allo KJR, Seufert L, Hohne M, Lucas C, Bock T, Isermann L, Brodesser S, Lackmann JW, Kiefer K, Koehler FC, Bohl K, Ignarski M, Schiller P, Johnsen M, Kubacki T, Grundmann F, Benzing T, Trifunovic A, Kruger M, Schermer B, Burst V, and Muller RU (2023). Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway. J Am Soc Nephrol 34, 772-792. doi:10.1681/ASN.0000000000000087.
     
  • Steiner JD, Annibal A, Laboy R, Braumann M, Gobel H, Laasch V, Muller RU, Spath MR, Antebi A, and Kubacki T (2023). A novel TNFRSF1A mutation associated with TNF-receptor-associated periodic syndrome and its metabolic signature. Rheumatology (Oxford) 62, 3459-3468. doi:10.1093/rheumatology/kead068.
     
  • van Heugten MH, Blijdorp CJ, Arjune S, van Willigenburg H, Bezstarosti K, Demmers JAA, Musterd-Bhaggoe U, Meijer E, Gansevoort RT, Zietse R, Hayat S, Kramann R, Muller RU, Salih M, Hoorn EJ, and Consortium D (2023). Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. doi:10.1681/ASN.0000000000000277.
     
  • Wahida A, Schmaderer C, Buttner-Herold M, Branca C, Donakonda S, Haberfellner F, Torrez C, Schmitz J, Schulze T, Seibt T, Ollinger R, Engleitner T, Haller B, Steiger K, Gunthner R, Lorenz G, Yabal M, Bachmann Q, Braunisch MC, Moog P, Matevossian E, Assfalg V, Thorban S, Renders L, Spath MR, Muller RU, Stippel DL, Weichert W, Slotta-Huspenina J, von Vietinghoff S, Viklicky O, Green DR, Rad R, Amann K, Linkermann A, Brasen JH, Heemann U, and Kemmner S (2023). High RIPK3 expression is associated with a higher risk of early kidney transplant failure. iScience 26, 107879. doi:10.1016/j.isci.2023.107879.
  • 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
Prof. Dr. Roman-Ulrich Müller

Medical Faculty, University of Cologne (UoC)

CMMC - PI - assoc. RG 13

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Medical Faculty, University of Cologne (UoC)

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Curriculum Vitae - Roman-Ulrich Müller
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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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