Disrupted glucocorticoid receptor cell signalling causes a ciliogenesis defect in the fetal mouse renal tubule

Abstract Primary cilia are cell signalling and environment sensing organelles and have important roles during embryogenesis and homeostasis. We demonstrate glucocorticoid signalling is essential for normal cilia formation in mouse and human renal tubules. RNA sequencing of E18.5 kidneys from glucocorticoid receptor (GR) null mice identified significant reductions in key ciliogenesis-related genes including Ccp110, Cep97, Cep290 and Kif3a. Confocal microscopy reveals abnormal, stunted cilia on proximal tubules, podocytes, and collecting duct cells in mice with global or conditional deletion of GR. In contrast, activation of GR signalling with dexamethasone in human kidney organoids or mouse IMCD3 cells increases cilia length, an effect blocked by the GR antagonist RU486. Analysis of GR-null kidney extracts demonstrates reduced levels of pERK and SUFU identifying potential cell pathway crosstalk with GR signalling that coordinately regulate ciliogenesis in the renal tubule. Finally, dexamethasone reduces Aurora kinase A levels, a factor driving cilia disassembly and implicated in the pathogenesis of polycystic kidney disease.