In the kidney, the spectrum of inflammatory diseases is broad, ranging from autoimmune diseases to podocytopathies such as focal segmental glomerulosclerosis (FSGS). Identification of common and distinct immunological pathways is key to understanding glomerular pathophysiology and developing targeted therapies.

In the past, we developed mouse models of metabolic stress by introducing a specific mutations in metabolic enzymes. In addition to developing a progressive nephrotic syndrome, these mice develop varying degrees of glomerular inflammation.

To understand the pathomechanisms responsible for renal inflammation, we will analyze the landscape of inflammatory mechanisms by flow cytometry, single-cell metabolic profiling and single-cell RNA sequencing. Second, we will deplete key immune cell subsets to determine their contribution to glomerulosclerosis. Finally, we will transfer our findings to the bedside utilizing our recently established glomerular disease biobank and perform targeted proteomic analysis from renal biopsies to identify key proinflammatory molecules in various glomerular diseases. These data are simultaneously complemented by state-of-the art multidimensional imaging techniques to visualize the inflammatory infiltrate associated with glomerular injury and to assign proteomic analysis targets to their subcellular location in the same biopsy sample. We strongly believe that this approach will help us to develop tailored treatment strategies for our patients.

Clinical Relevance

Chronic kidney disease is a significant health and socioeconomic problem. Many inflammatory diseases affect the kidney's filtering unit causing irreversible damage. While immunosuppression remains a mainstay of therapy, lack of knowledge regarding the origins of the inflammatory signal hinders the development of targeted treatment strategies. The proposed studies will examine the contribution of myeloid immune cells in glomerular disease and will therefore make a significant contribution to the understanding of the pathophysiology of these complex diseases. Our project has a strong translational aspect by using state-of-the art proteomics and imaging techniques in order to accelerate the development of precision medicine strategies for our patients.

Approach

Analysis of immune cell subsets in kidney, spleen and renal lymph nodes
Determining the contribution of pro-inflammatory and anti-inflammatory myeloid cells in glomerular diseases
Deciphering the contribution of metabolic and inflammatory signaling pathways in glomerular disease by combining targeted proteomics and imaging mass cytometry of human kidney biopsy samples

Figure 1

Fig. 1: CYTOF (Cytometry by time of flight) from a patient with chronic kidney disease.

Figure 2

Fig. 2: Imaging Mass Cytometry of a kidney biopsy core. CD16+ Monocytes (white arrow) und CD4+ T-helper cells (red arrow).

Figure 3

Fig. 3: Clustering of glomerular cells by single cell RNAseq.

Lab Website

For more information, please check Prof. Brinkkötter´s and Dr. Brähler´s site.

Affiliations - Sebastian Brähler

Publication Record on PubMed - Paul Brinkkötter

Publication Record on PubMed - Sebastian Brähler

Publications generated during 1/2023-12/2025 with CMMC affiliation

2024 (up to June)

Hurcombe JA, Barrington F, Marchetti M, Betin VMS, Bowen EE, Lay AC, Ni L, Dayalan L, Pope RJP, Brinkkoetter PT, Holzenberger M, Welsh GI, and Coward RJM (2024). Contrasting consequences of podocyte insulin-like growth factor 1 receptor inhibition. iScience27, 109749. doi:10.1016/j.isci.2024.109749.
Kaufeld JK, Kuhne L, Schonermarck U, Brasen JH, von Kaisenberg C, Beck BB, Erger F, Bergmann C, von Bergwelt-Baildon A, Brinkkotter PT, Volker LA, and Menne J (2024). Features of Postpartum Hemorrhage-Associated Thrombotic Microangiopathy and Role of Short-Term Complement Inhibition. Kidney Int Rep9, 919-928. doi:10.1016/j.ekir.2024.01.035.
Lindemann CH, Burst V, Völker LA, Brähler S, Simic D, Becker I, Hellmich M, Kurscheid C, Scholten N, Krauspe R, Leibel K, Stock S, Brinkkoetter PT. Personalized, interdisciplinary patient pathway for cross-sector care of multimorbid patients (eliPfad trial): study protocol for a randomized controlled trial. Trials. 2024 Mar 11;25(1):177. doi: 10.1186/s13063-024-08026-8. PMID: 38468319; PMCID: PMC10926660.
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.
Schonfelder K, Kuhne L, Schulte-Kemna L, Kaufeld J, Rohn H, Kribben A, Schroppel B, Brinkkotter PT, and Gackler A (2024). Clinical efficacy and safety of switching from eculizumab to ravulizumab in adult patients with aHUS- real-world data. BMC Nephrol25, 202. doi:10.1186/s12882-024-03638-3.

2023

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.
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.
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.

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