Polycystic kidney diseases (PKD) affect millions of people worldwide and are the major genetic cause of kidney replacement therapy (KRT) in both children and adults. The two major types of PKD are the more common autosomal-dominant polycystic kidney disease (ADPKD), mainly caused by variants in the PKD genes PKD1 and PKD2, and the rare pediatric autosomal-recessive polycystic kidney disease (ARPKD), mainly caused by PKHD1 variants.

Notably, there is clinical and genetic overlap between ARPKD and ADPKD. All three genes encode for proteins localized to primary cilia. Cilia are sensory organelles that in the kidney project from the apical membrane of epithelial cells into the lumen of the tubules. PKD is generally regarded as a paradigm ciliopathy. In contrast to ADPKD, for which a first disease-modifying pharmacological therapy has been established, there is currently no targeted therapy for ARPKD.

PKHD1 encodes for the large ciliary transmembrane protein fibrocystin (FC). Disease-causing variants in PKHD1 have been described almost across the entire gene. By analyzing longitudinal clinical data of hundreds of ARPKD patients in a large multinational collaborative effort, we could recently gain significant insights into the genotype-phenotype correlation of ARPKD patients. We could show that missense variants in specific areas of the gene are associated with better kidney survival. With the ARegPKD registry initiated by one of the applicants, we have full access to the largest clinical ARPKD database worldwide. Moreover, we could generate and confirm the recently described first Pkhd1-associated preclinical model of ARPKD that results in a kidney and liver phenotype recapitulating human ARPKD.

Using a translational approach by combining our novel insights into genotype-phenotype correlations with available with the novel mammalian in vivo model, we follow the overarching aim to uncover the mechanisms of how variants in Pkhd1 result in PKD by affecting primary cilia and transcriptional programs in kidney cells. In particular, we aim to understand why variants affecting some parts of FC result in rapid progression of kidney disease while others affect kidneys much later in life. Specifically, we will (1) analyze on the cellular level how individual missense variants in Pkhd1 affect FC function and the transcriptome of kidney epithelial cells, (2) investigate FC-related regulation of the ciliary protein composition in vitro and in vivo, and (3) study how missense and null variants in PKHD1/Pkhd1 affect cell type specific signaling in kidneys. Ultimately, we aim to contribute to the development of novel disease-modifying therapeutic concepts for ARPKD.

Clinical Relevance

Autosomal-recessive polycystic kidney disease (ARPKD) is a severe and early-onset pediatric disease characterized by fibrocystic changes in kidneys and the liver. It is a major cause of chronic kidney disease and kidney failure in children requiring dialysis or transplantation. There is no targeted therapy yet as the molecular pathogenesis is not well understood. Here, we aim to combine the power of clinical knowledge obtained from a pan-European registry study with state-of-the-art preclinical models, cellular biochemical approaches, and single-cell transcriptomics to identify the relevant pathways that distinguish between early and late renal involvement. We anticipate that our work will result in a deeper disease understanding paving the way for strategies to delay the onset and progression of kidney disease in ARPKD and additional renal ciliopathies.

Approach

Overall approach of the suggested project

Kidney findings in ARPKD and research questions of the project

Affiliations - Max C Liebau

Publication Record on PubMed - Max C Liebau

Publication Record on PubMed - Bernhard Schermer

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

2024 (up to June)

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.

2023

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.
Burgmaier K, Broekaert IJ, and Liebau MC (2023). Autosomal Recessive Polycystic Kidney Disease: Diagnosis, Prognosis, and Management. Adv Kidney Dis Health 30, 468-476. doi:10.1053/j.akdh.2023.01.005.
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.
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.
Etich J, Semler O, Stevenson NL, Stephan A, Besio R, Garibaldi N, Reintjes N, Dafinger C, Liebau MC, Baumann U, Morgelin M, Forlino A, Stephens DJ, Netzer C, Zaucke F, and Rehberg M (2023). TAPT1-at the crossroads of extracellular matrix and signaling in Osteogenesis imperfecta. EMBO Mol Med 15, e17528. doi:10.15252/emmm.202317528.
Gopalakrishnan J, Feistel K, Friedrich BM, Grapin-Botton A, Jurisch-Yaksi N, Mass E, Mick DU, Muller RU, May-Simera H, Schermer B, Schmidts M, Walentek P, and Wachten D (2023). Emerging principles of primary cilia dynamics in controlling tissue organization and function. EMBO J 42, e113891. doi:10.15252/embj.2023113891.
Halawi AA, Burgmaier K, Buescher AK, Dursun I, Erger F, Galiano M, Gessner M, Gokce I, Mekahli D, Mir S, Obrycki L, Shroff R, Stabouli S, Szczepanska M, Teixeira A, Weber LT, Wenzel A, Wuhl E, Zachwieja K, Dotsch J, Schaefer F, and Liebau MC (2023). Clinical Characteristics and Courses of Patients With Autosomal Recessive Polycystic Kidney Disease-Mimicking Phenocopies. Kidney Int Rep 8, 1449-1454. doi:10.1016/j.ekir.2023.04.006.
Harafuji N, Yang C, Wu M, Thiruvengadam G, Gordish-Dressman H, Thompson RG, Bell PD, Rosenberg AZ, Dafinger C, Liebau MC, Bebok Z, Caldovic L, and Guay-Woodford LM (2023). Differential regulation of MYC expression by PKHD1/Pkhd1 in human and mouse kidneys: phenotypic implications for recessive polycystic kidney disease. Front Cell Dev Biol 11, 1270980. doi:10.3389/fcell.2023.1270980.
Liebau MC, Mekahli D, Perrone R, Soyfer B, and Fedeles S (2023). Polycystic Kidney Disease Drug Development: A Conference Report. Kidney Med 5, 100596. doi:10.1016/j.xkme.2022.100596.
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.
Mekahli D, Liebau MC, Cadnapaphornchai MA, Goldstein SL, Greenbaum LA, Litwin M, Seeman T, Schaefer F, and Guay-Woodford LM (2023). Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease. BMC Nephrol 24, 33. doi:10.1186/s12882-023-03072-x.
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.
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.
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.
Zed SEA, Hackl A, Bohl K, Ebert L, Kieckhöfer E, Müller C, Becker K, Fink G, Nüsken KD, Nüsken E, Müller RU, Schermer B, and Weber LT (2023). Mycophenolic acid directly protects podocytes by preserving the actin cytoskeleton and increasing cell survival. Scientific Reports 13. doi:Artn 428110.1038/S41598-023-31326-Z.

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