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Abstract: PO1690

Simultaneous Loss of Podocyte Insulin Receptor (IR) and Insulin-Like Growth Factor 1 Receptor (IGF1R) Is Detrimental and Associated with Spliceosome Dysfunction

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Hurcombe, Jenny, University of Bristol, Bristol, Bristol, United Kingdom
  • Dayalan, Lusyan, University of Bristol, Bristol, Bristol, United Kingdom
  • Barrington, Fern, University of Bristol, Bristol, Bristol, United Kingdom
  • Ni, Lan, University of Bristol, Bristol, Bristol, United Kingdom
  • Brinkkoetter, Paul T., Uniklinik Koln, Koln, Nordrhein-Westfalen, Germany
  • Holzenberger, Martin, INSERM, Paris, Île-de-France, France
  • Welsh, Gavin Iain, University of Bristol, Bristol, Bristol, United Kingdom
  • Coward, Richard, University of Bristol, Bristol, Bristol, United Kingdom
Background

Insulin signalling to the podocyte via the insulin receptor (IR) is crucial for kidney function. Insulin-like growth factor 1 (IGF1) signalling through the structurally related insulin-like growth factor 1 receptor (IGF1R) is also known to directly affect the podocyte. Since the IR and IGF1R may act redundantly in some contexts, this study sought to elucidate the compound role of the insulin/IGF1 axis in podocyte function using mouse and cell culture models deficient in both receptors.

Methods

To examine the effects of combined receptor loss in vivo, a transgenic mouse model with conditional inactivation of podocyte IR and IGF1R was generated. In vitro, conditionally immortalised genetic IR knockout, IGF1R knockout and IR/IGF1R dual knockout podocytes were characterised using global proteomic and transcriptomic analysis.

Results

Podocyte specific IR/IGF1R knockout mice developed significant albuminuria and a severe renal phenotype with global sclerosis, renal failure and death occurring between 4 and 24 weeks.
>90% loss of IR/IGF1R in cultured mouse podocytes was also detrimental resulting in >50% cell death 7 days after gene knockdown. Enrichment analysis of total proteomic data revealed a striking downregulation of gene ontology terms associated with splicing and RNA processing activity in IR/IGF1R knockout cells. Western blot analysis was used to validate the reduced expression of proteins responsible for spliceosome synthesis and regulation in dual knockout podocytes, including polypyrimidine tract-binding protein 2 (PTBP2), eukaryotic initiation factor 4A (EIF4A) and splicing factor 3B subunit 4 (SF3B4).

Conclusion

This work underlines the critical importance of podocyte insulin/IGF signalling and reveals a novel role for this signalling axis in RNA processing by regulating spliceosome activity.

Funding

  • Government Support – Non-U.S.