Arp2/3-dependent regulation of ciliogenesis governs adaptive distal tubular epithelial cell states in kidney disease
Proteinuric kidney disease substantially affects renal tubules through incompletely understood mechanisms. We identify elongation of primary cilia in distal renal tubules in the context of glomerular nephropathy. In renal biopsies and mouse models, tubular injury correlates with ciliary elongation, tubule dilation, and disruption of the cortical actin cytoskeleton. In vitro studies implicate biophysical cues of the glomerular filtrate and subsequent dysregulation of the actin cytoskeleton as contributing factors, confirmed by conditional deletion of N-WASP and Arp2/3 in vivo and in vitro. Electron and fluorescence microscopy revealed enlarged ciliary pockets, basal body mislocalization, and intracellular cilia formation in <i>Arp3</i> knockout conditions. Transcriptome analysis identifies the essential role of cilia in maintaining adaptive tubular cell states, while persistent activation leads to disease progression through extracellular matrix remodeling, exemplified by Tenascin-C. Our findings establish cilia as central mediators of tubular adaptation to injury and identify the Arp2/3-dependent actin cytoskeleton as a critical regulator, providing essential insights into the pathogenesis of chronic kidney disease.
Authors
- Alena Sammarco
- Katja Gräwe
- August Sigle (ORCID: https://orcid.org/0000-0001-6857-8149)
- Suresh Krishna Ramakrishnan
- Wibke Bechtel‐Walz (ORCID: https://orcid.org/0000-0001-6032-3627)
- Grigor Andreev (ORCID: https://orcid.org/0009-0008-3808-8331)
- Manuel Rogg (ORCID: https://orcid.org/0000-0002-6658-9159)
- Markus Grabbert (ORCID: https://orcid.org/0000-0002-7059-6124)
- Thomas Benzing (ORCID: https://orcid.org/0000-0003-0512-1066)
- Oliver Schilling (ORCID: https://orcid.org/0000-0001-7678-7653)
- Matias Simons (ORCID: https://orcid.org/0000-0003-3959-6350)
- Yakup Tanriver (ORCID: https://orcid.org/0000-0002-4806-2548)
- Linus Butt (ORCID: https://orcid.org/0000-0002-2568-2998)
- Tobias B. Huber (ORCID: https://orcid.org/0000-0001-7175-5062)
- Christoph Schell (ORCID: https://orcid.org/0000-0001-5344-624X)
- Oliver Kretz (ORCID: https://orcid.org/0000-0003-1152-5956)
- Jasmin I. Maier (ORCID: https://orcid.org/0000-0003-4158-2935)
- Martin Werner
- Paul Thomas Brinkkoetter (ORCID: https://orcid.org/0000-0002-4287-2080)
- Martin Helmstädter (ORCID: https://orcid.org/0000-0001-6027-0094)
- Frederic Arnold (ORCID: https://orcid.org/0000-0001-6799-9152)
- Lisa Weißer
- Charlotte Kark
- Cem Özel (ORCID: https://orcid.org/0009-0006-7091-7027)
- Marlene Stigler
Institutions
- Universität Hamburg (DE)
- University of Freiburg (DE)
- University of Cologne (DE)
- Heidelberg University (DE)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Institute of Medical Microbiology and Hygiene (DE)
- University Hospital Cologne (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1126/sciadv.ady1623
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00