The Insulin/Insulin-Like Growth Factor Axis Is Critically Important in the Podocyte and Controls Gene Transcription and Spliceosome Function

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Background: Insulin signalling to the podocyte via the cognate insulin receptor (IR) is crucial for kidney function and 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 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 immortalized genetic IR/IGF1R dual knockout podocytes were characterised using proteomic, transcriptomic and metabolomic 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 the IR and IGF1R in cultured mouse podocytes was also detrimental resulting in >50% cell death 7 days after receptor gene excision. Enrichment analysis of total proteomic data revealed a striking downregulation of gene ontology terms associated with splicing and RNA processing activity in IR/IGF1R deficient cells. Genome-wide and targeted long-read RNA sequencing was performed to further explore the effect of dual receptor suppression on spliceosome function alongside metabolomic studies to elucidate key metabolic pathways regulated by these receptors. Conclusions: 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.

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