The insulin / IGF axis is critically important controlling gene transcription in the podocyte.

Hurcombe, J. A.; Dayalan, L.; Barrington, F.; Burdet, F.; Ni, L.; Coward, J. T.; Brinkkoetter, P.; Holzenberger, M.; Jeffries, A. R.; Oltean, S.; Welsh, G. I.; Coward, R. J.

doi:10.1101/2024.05.20.594973

bioRxiv · 10.1101/2024.05.20.594973

The insulin / IGF axis is critically important controlling gene transcription in the podocyte.

Hurcombe, J. A.·Dayalan, L.·Barrington, F.·Burdet, F.·Ni, L.·Coward, J. T.·Brinkkoetter, P.·Holzenberger, M.·Jeffries, A. R.·Oltean, S.·Welsh, G. I.·Coward, R. J.

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Abstract

Signalling to the podocyte via the structurally related insulin receptor (IR) or insulin-like growth factor 1 receptor (IGF1R) is important for podocyte function. This study sought to elucidate the compound role of the insulin/IGF1 axis in podocytes using transgenic mice and cell culture models deficient in both receptors. Podocyte specific IR/IGF1R knockdown mice developed a severe kidney phenotype with albuminuria, glomerulosclerosis and renal failure with death occurring in some mice between 4 and 24 weeks. Simultaneous knockdown of both receptors in cultured podocytes resulted in >50% cell death by 7 days. Proteomic analysis revealed a striking downregulation of spliceosome-related proteins in IR/IGF1R knockdown podocytes with long-read RNA sequence data indicating an increased fraction of transcripts with intron retention/premature termination codons in these cells. Furthermore, phospho-proteomic analysis revealed multiple insulin / IGF1 induced spliceosomal post-translational protein and kinase modifications suggesting dynamic control of this system. This study underlines the importance of podocyte insulin/IGF signalling demonstrating a novel role for this extrinsic hormonal signalling axis in regulating gene transcription in this cell type.

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Hurcombe, J. A., Dayalan, L., Barrington, F., Burdet, F., Ni, L., Coward, J. T., Brinkkoetter, P., Holzenberger, M., Jeffries, A. R., Oltean, S., Welsh, G. I., Coward, R. J.. 2024-05-21. The insulin / IGF axis is critically important controlling gene transcription in the podocyte.. https://doi.org/10.1101/2024.05.20.594973

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