Benzing, Thomas - C 01

Pressure-dependent proteostasis regulation in podocytes at the kidney filtration barrier and the pathogenesis of albuminuria

Prof. Dr. Thomas Benzing
Prof. Dr. Thomas Benzing

Clinic II for Internal Medicine

CMMC - Chair
CMMC - PI - C 01

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Clinic II for Internal Medicine

Center for Molecular Medicine Cologne Robert-Koch-Str. 21

50931 Cologne

Introduction

Chronic kidney disease (CKD) is becoming an increasingly prevalent condition affecting almost 10% of the population in Western societies. Most kidney diseases that progress to CKD start in the glomerulus, the renal filtration unit, due to a limited capacity of glomeruli for regeneration and the limited ability of terminally differentiated glomerular podocytes for self-renewal. Podocytes enwrap the glomerular capillaries, and elaborate primary and interdigitating secondary extensions connected by a membrane-like cell junction called the slit diaphragm. Together with the underlying glomerular basement membrane and specialized fenestrated glomerular endothelial cells, podocytes constitute the kidney filter.

Over the past decade, we showed that proteins residing at the slit diaphragm form an evolutionarily conserved mechanosensitive multiprotein complex that controls podocyte morphology, viability and function.

Recently, our group's super-resolution STED imaging of CRISPR-genetically engineered mouse models of human disease revealed the biophysical basis of glomerular ultrafiltration. These data now explain how podocyte ultrastructural changes may translate into albuminuria: Podocyte ultrastructural simplification and shortening of the slit diaphragm cause loss of buttress forces of podocytes to counteract capillary blood pressure. Diminished buttress forces result in decompression of the GBM and loss of the size-selective barrier. However, the link between cell injury and podocyte ultrastructural changes remains elusive.

Here we will (1) study the role of two evolutionarily conserved ubiquitylation machines containing HUWE1 or Ubr4 and associated proteins in mediating disease-related proteostasis defects that cause ultrastructural failure, and (2) examine the dynamic crosstalk of slit diaphragm and cytoskeletal proteins in glomerular disease in vivo.

Clinical Relevance

Injury to podocytes causes loss of buttress forces, decompression of the GBM, and failure of the glomerular filter. The proposed project will now link podocyte deregulated signaling and altered protein homeostasis with cytoskeletal changes and ultrastructural podocyte alterations. Clinically, this is most relevant as drugs that are able to reduce mechanical strain (such as SGLT2 inhibitors and renin-angiotensin system blockers) have the potential to alleviate disease and prevent end-stage renal failure. Thus, the development of targeted interventions to support podocyte mechanical stability is the most promising therapeutic approach in glomerular disease treatment.

Approach

  • Understanding the role of HUWE and Ubr4 in podocyte homeostasis using in vivo models
  • Deciphering the crosstalk of the cytoskeleton and the slit-diaphragm protein complex
  • Multiomic analyses of glomerular cells from disease models

Lab Website

For more information, please check the research website. 

Affiliations

Publication Record on PubMed - Thomas Benzing

2024 (up to June)
  • Czogalla J, Schliffke S, Lu S, Schwerk M, Petereit H, Zhang T, Liu S, Dumoulin B, Gies S, Wu G, Hanzelmann S, Bode M, Grahammer F, Godel M, Voigtlander M, Butt L, Bokemeyer C, Bergmann C, Benzing T, Wiech T, Puelles VG, and Huber TB (2024). Ibrutinib-associated focal segmental glomerulosclerosis and the impact of podocin mutations in chronic lymphocytic leukemia. Kidney Int105, 877-881. doi:10.1016/j.kint.2024.02.001.
     
  • Ferring A, Muck L, Stegemann J, Wiebe L, Becker I, Benzing T, Meyer AM, and Polidori MC (2024). Prognostic Features of Sarcopenia in Older Hospitalized Patients: A 6-Month Follow-Up Study. J Clin Med13. doi:10.3390/jcm13113116.
     
  • Nies JF, Hendrix C, Bartram MP, Spear R, Hagmann H, Benzing T, and Kubacki T (2024). Effectiveness and safety of immunoadsorption as a rescue treatment of inflammatory myopathies: report of three cases and literature review. Ther Adv Musculoskelet Dis16, 1759720X241250238. doi:10.1177/1759720X241250238.
     
  • Schomig T, Diefenhardt P, Plagmann I, Trinsch B, Merz T, Crispatzu G, Unnersjo-Jess D, Nies J, Putz D, Sierra Gonzalez C, Schermer B, Benzing T, Brinkkoetter PT, and Brahler S (2024). The podocytes' inflammatory responses in experimental GN are independent of canonical MYD88-dependent toll-like receptor signaling. Sci Rep14, 2292. doi:10.1038/s41598-024-52565-8.
     
  • Wiesner E, Binz-Lotter J, Hackl A, Unnersjo-Jess D, Rutkowski N, Benzing T, and Hackl MJ (2024). Correlative multiphoton-STED microscopy of podocyte calcium levels and slit diaphragm ultrastructure in the renal glomerulus. Sci Rep14, 13019. doi:10.1038/s41598-024-63507-9.
2023
  • 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.
     
  • Butt L, Unnersjo-Jess D, Reilly D, Hahnfeldt R, Rinschen MM, Bozek K, Schermer B, Benzing T, and Hohne M (2023). In vivo characterization of a podocyte-expressed short podocin isoform. BMC Nephrol 24, 378. doi:10.1186/s12882-023-03420-x.
     
  • 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.
     
  • Debes C, Papadakis A, Gronke S, Karalay O, Tain LS, Mizi A, Nakamura S, Hahn O, Weigelt C, Josipovic N, Zirkel A, Brusius I, Sofiadis K, Lamprousi M, Lu YX, Huang W, Esmaillie R, Kubacki T, Spath MR, Schermer B, Benzing T, Muller RU, Antebi A, Partridge L, Papantonis A, and Beyer A (2023). Ageing-associated changes in transcriptional elongation influence longevity. Nature 616, 814-821. doi:10.1038/s41586-023-05922-y.
     
  • Diefenhardt P, Braumann M, Schomig T, Trinsch B, Sierra Gonzalez C, Becker-Gotot J, Volker LA, Ester L, Mandel AM, Hawiger D, Abdallah AT, Schermer B, Gobel H, Brinkkotter P, Kurts C, Benzing T, and Brahler S (2023). Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis. J Am Soc Nephrol 34, 1366-1380. doi:10.1681/ASN.0000000000000159.
     
  • Ester L, Cabrita I, Ventzke M, Kieckhofer E, Christodoulou M, Mandel AM, Diefenhardt P, Fabretti F, Benzing T, Habbig S, and Schermer B (2023). The role of the FSGS disease gene product and nuclear pore protein NUP205 in regulating nuclear localization and activity of transcriptional regulators YAP and TAZ. Hum Mol Genet 32, 3153-3165. doi:10.1093/hmg/ddad135.
     
  • Gill D, Zagkos L, Gill R, Benzing T, Jordan J, Birkenfeld AL, Burgess S, and Zahn G (2023). The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development. BMC Med 21, 504. doi:10.1186/s12916-023-03227-5.
     
  • Hagmann H, Khayyat NH, Matin M, Oezel C, Chen H, Schauss A, Schell C, Benzing T, Dryer S, and Brinkkoetter PT (2023). Capsazepine (CPZ) Inhibits TRPC6 Conductance and Is Protective in Adriamycin-Induced Nephropathy and Diabetic Glomerulopathy. Cells 12. doi:10.3390/cells12020271.
     
  • Lenz M, Harland A, Egenolf P, Horbach M, von Hodenberg C, Brinkkoetter PT, Benzing T, Eysel P, and Scheyerer MJ (2023). Correlation between kidney function and mortality in pyogenic spondylodiscitis: the glomerular filtration rate (GFR) as new predictive parameter? Eur Spine J 32, 1455-1462. doi:10.1007/s00586-023-07578-8.
     
  • Llamas E, Koyuncu S, Lee HJ, Wehrmann M, Gutierrez-Garcia R, Dunken N, Charura N, Torres-Montilla S, Schlimgen E, Mandel AM, Theile EB, Grossbach J, Wagle P, Lackmann JW, Schermer B, Benzing T, Beyer A, Pulido P, Rodriguez-Concepcion M, Zuccaro A, and Vilchez D (2023). In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation. Nat Aging 3, 1345-1357. doi:10.1038/s43587-023-00502-1.
     
  • Odenthal J, Dittrich S, Ludwig V, Merz T, Reitmeier K, Reusch B, Hohne M, Cosgun ZC, Hohenadel M, Putnik J, Gobel H, Rinschen MM, Altmuller J, Koehler S, Schermer B, Benzing T, Beck BB, Brinkkotter PT, Habbig S, and Bartram MP (2023). Modeling of ACTN4-Based Podocytopathy Using Drosophila Nephrocytes. Kidney Int Rep 8, 317-329. doi:10.1016/j.ekir.2022.10.024.
     
  • Osterholt T, Todorova P, Kuhne L, Ehren R, Weber LT, Grundmann F, Benzing T, Brinkkotter PT, and Volker LA (2023). Repetitive administration of rituximab can achieve and maintain clinical remission in patients with MCD or FSGS. Sci Rep 13, 6980. doi:10.1038/s41598-023-32576-7.
     
  • 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.
     
  • Todorova P, Arjune S, Hendrix C, Oehm S, Schmidt J, Krauss D, Burkert K, Burst VR, Benzing T, Boehm V, Grundmann F, and Müller RU (2023). Interaction Between Determinants Governing Urine Volume in Patients With ADPKD on Tolvaptan and its Impact on Quality of Life. Kidney International Reports 8, 1616-1626. doi:10.1016/j.ekir.2023.05.011.
     
  • Unnersjo-Jess D, Butt L, Hohne M, Sergei G, Fatehi A, Witasp A, Wernerson A, Patrakka J, Hoyer PF, Blom H, Schermer B, Bozek K, and Benzing T (2023). Deep learning-based segmentation and quantification of podocyte foot process morphology suggests differential patterns of foot process effacement across kidney pathologies. Kidney Int 103, 1120-1130. doi:10.1016/j.kint.2023.03.013.
     
  • Unnersjo-Jess D, Ramdedovic A, Butt L, Plagmann I, Hohne M, Hackl A, Brismar H, Blom H, Schermer B, and Benzing T (2023). Advanced optical imaging reveals preferred spatial orientation of podocyte processes along the axis of glomerular capillaries. Kidney Int 104, 1164-1169. doi:10.1016/j.kint.2023.08.024.

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