The insulin/IGF axis is critically important for controlling gene transcription in the podocyte
Podocyte integrity depends critically on signalling through the insulin receptor and IGF1 receptor , and this study defines their combined importance using dual-receptor knockdown in mice and cultured podocytes. Podocyte-specific reduction of both receptors in transgenic mice caused kidney disease characterised by albuminuria and glomerulosclerosis, with premature death occurring in some animals between 4 and 24 weeks. Receptor-deficient cultured podocytes exhibited >50% cell loss within 7 days. Integrated proteomic and transcriptomic analyses revealed marked depletion of spliceosome-associated proteins and widespread intron retention with premature termination codons, indicating profound disruption of RNA processing. Phospho-proteomic profiling further showed that insulin/IGF1 stimulation induces dynamic post-translational modifications across spliceosomal components and regulatory kinases. Together, these findings uncover a previously unrecognised role for podocyte insulin/IGF1 signalling in maintaining spliceosomal integrity and transcriptional fidelity, establishing this hormonal axis as a key extrinsic regulator of podocyte gene expression.
Authors
- Mark Ibberson (ORCID: https://orcid.org/0000-0003-3152-5670)
- Fern Barrington (ORCID: https://orcid.org/0000-0001-7521-7712)
- Gavin I. Welsh (ORCID: https://orcid.org/0000-0002-2148-6658)
- Sebastian Oltean (ORCID: https://orcid.org/0000-0001-7890-8439)
- Lusyan Dayalan (ORCID: https://orcid.org/0000-0003-0821-9149)
- Martin Holzenberger (ORCID: https://orcid.org/0000-0003-4869-725X)
- Jenny Hurcombe (ORCID: https://orcid.org/0000-0002-4064-7306)
- Aaron R. Jeffries (ORCID: https://orcid.org/0000-0002-1235-8291)
- Richard J. Coward (ORCID: https://orcid.org/0000-0001-6183-2546)
- Frédéric Burdet (ORCID: https://orcid.org/0000-0002-2923-827X)
- Paul Thomas Brinkkoetter (ORCID: https://orcid.org/0000-0002-4287-2080)
- Lan Ni (ORCID: https://orcid.org/0000-0002-4733-5081)
- Joseph Talih Coward (ORCID: https://orcid.org/0009-0004-5416-3099)
Institutions
- SIB Swiss Institute of Bioinformatics (CH)
- Université Paris Cité (FR)
- University of Exeter (GB)
- University of Bristol (GB)
- Institut Necker Enfants Malades (FR)
- Düsseldorf University Hospital (DE)
- Sorbonne Paris Cité (FR)
- NIHR Exeter Clinical Research Facility (GB)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Health & Life (Taiwan) (TW)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- eLife
- Published
- 2026-09-04
- DOI
- https://doi.org/10.7554/elife.107791.5
- Primary Topic
- Renal Diseases and Glomerulopathies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Federation of Pharmaceutical Industries and Associations
- Kidney Research UK
- European Commission
- University of Bristol
- Medical Research Council
- HORIZON EUROPE Health