Hedgehog signaling is non-cell autonomously activated in the cystic kidney of Arl13b mutant mice

ABSTRACT Background Polycystic kidney disease (PKD) is a ciliopathy characterized by fluid-filled epithelial cysts in the kidney. Although it is well established that the primary cilium is essential for Hedgehog (HH) signalling and HH signalling is abnormally activated in cystic kidneys of multiple PKD models, the mechanism and function of HH activation in PKD pathogenesis remains incompletely understood. Methods We used a transgenic HH reporter line to identify the target tissue of HH signalling in Arl13 f/f ;Ksp-Cre mutant kidney, in which the cilia biogenesis gene Arl13b is specifically deleted in epithelial cells of the distal nephron. In addition, we treated Arl13b f/f ;Ksp-Cre mice with the GLI inhibitor GANT61 and analyzed its impact on PKD progression in this model. Results In vivo in the mouse kidney, deletion of Arl13b in epithelial cells led to non-cell autonomous activation of the HH pathway in the interstitium. In addition, whole body inhibition of the HH pathway by GANT61 reduced cyst burden, suppressed fibrosis and reduced kidney function decline in Arl13b f/f ;Ksp-Cre mice. Conclusions Our results reveal non-cell autonomous activation of HH signalling in the interstitium of the cystic kidney of Arl13b f/f ;Ksp-Cre mice and suggest that abnormal activation of the HH pathway contributes to PKD progression.