The renal inflammatory network of nephronophthisis.

Nephronophthisis (NPH) and autosomal dominant polycystic kidney disease (ADPKD) are caused by mutations in genes encoding primary cilia proteins. In ADPKD, altered cilia signaling promotes renal inflammation through the upregulation of the macrophage chemoattractant CCL2, which subsequently fuels disease progression. While inactivation of NPHP1, the main gene involved in NPH leads to increased CCL2 expression in cultured renal epithelial cells, little is known about renal inflammation in NPH. Here, we analyzed murine models of NPH as well as kidney tissues and urine derived renal epithelial cells (UREC) from NPH patients to dissect the renal inflammatory network involved in NPH. Similarly to ADPKD, NPH patients present kidney infiltration by macrophages, increased CCL2 expression by tubular cells and enhanced CCL2 urinary excretion. Yet, while tubule specific Ccl2 disruption dramatically reduced renal Ccl2 expression in a mouse model of NPH, this did not translate into reduced macrophage infiltration nor lessened renal deterioration. In further contrast to early ADPKD, infiltrating macrophages were accompanied by neutrophils and T cells in both human and murine NPH. Through analysis of transcriptome datasets from early diseased kidneys in two distinct mouse models of NPH, we identified a set of 17 soluble inflammatory mediators, which increased independently of CCL2. Among those, 8 were also significantly upregulated in UREC from NPH patients compared to controls. Collectively, these results unveil that mutations in ciliary proteins in NPH and ADPKD trigger divergent renal inflammatory responses. This work sheds light on the specific inflammatory network underlying NPH.