Long-read (ONT) RNA-seq of Insr/Igf1r double-knockout and wild-type mouse podocytes — Related to eLife paper The insulin / IGF axis is critically important for controlling gene transcription in the podocyte.

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.