Primary cilia control kidney inflammation and scarring in response to obstruction

Abstract

Primary cilium is a unique antenna‐like structure that protrudes from the surface of most mammalian cells. Primary cilia are located at the apical surface of renal tubular epithelial cells, where they are bathed in the forming urine. Overall, primary cilia are signaling platforms that integrate mechanical and chemical cues. Yet, the functions of tubular cells cilia in kidney physiology remain unclear. Mutations in genes encoding ciliary proteins frequently lead to the development of chronic kidney diseases such as Autosomal Dominant Polycystic Kidney Disease or Nephronophthisis. A common denominator of these “renal ciliopathies” is the infiltration of the kidney by immune cells and myofibroblasts that prompt renal scarring. In the absence of mutations, such events can notably be triggered by tubular obstruction, which abolished urinary flux and therefore may affect cilia signaling. Yet the contribution of primary cilia in kidney response to obstruction is unknown.Here, we combined comparative analysis of kidney gene expression datasets, models of mechanical tubular obstruction and genetic ablation of primary cilia to explore this question. Our results indicate that the renal cytokine landscape of ciliopathies massively overlaps with the one induced by ureteral obstruction. Applying this latter model to mice with tubule specific cilia ablation, we demonstrated that cilia are instrumental in the induction of most of these cytokines. Subsequently cilia ablation mitigated macrophage and neutrophil recruitment to the kidney and reduced fibrosis burden.All together, these results show that primary cilia evoke a coordinated response to tubular obstruction reminiscent of genetic renal ciliopathies. Elucidating the mechanisms underlying this function of primary cilia may illuminate the pathophysiology of both genetic and non‐genetic chronic kidney diseases.AA* and AV* these authors equally contributed to this work