Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Disrupted glucocorticoid receptor-mediated signalling causes a primary cilia defect in the fetal mouse renal tubule (#82)

Jianshen Lao 1 , Kelly L Short 1 , Judy Ng 1 , Denny L Cottle 2 , Timothy J Cole 1
  1. Department of Biochemistry & Molecular Biology, Monash Biomedicine Discovery Institute, Clayton, Vic, Australia
  2. Department of Anatomy & Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, Vic, Australia

Primary cilia are microtubule-based organelles that protrude from cell membranes to mediate diverse developmental signalling pathways and senses extracellular stimuli to maintain tissue homeostasis. We show that glucocorticoid (GC) signaling via the glucocorticoid receptor (GR) is a regulator of normal primary cilia formation in kidney renal tubules. RNA sequencing of mice with global deletion of the GR (GR-null) identified significant reduced expression of key ciliogenesis-related genes; Ccp110 (fold -2.17), Cep97 (fold -1.79), Cep290 (fold -2.90), Kif3a (fold -1.82) and Rpgr (fold -1.87). Confocal microscopy revealed abnormal, stunted primary cilia in renal proximal tubules, collecting ducts and podocytes in GR-null or in conditional GR-deleted mice. Primary cilia length was significantly decreased in kidney proximal tubule cells in GR-null mice (5.21 ± 0.22μm) compared with wildtype controls (6.80 ± 0.59μm). In contrast, activation of GR signaling with the synthetic GC dexamethasone in mouse IMCD3 kidney tubule cells significantly increased primary cilia length (2.89 ± 0.04μm) compared with vehicle controls (2.46 ± 0.28μm), an effect blocked by the GR antagonist RU486. Together, these results demonstrate that GC signalling via the GR is required for normal primary ciliogenesis in the developing renal tubule and suggests that synthetic GR agonists may provide a novel therapeutic option for human ciliopathies such as those observed in forms of polycystic kidney disease.