Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

Significance Statement Polycystin proteins function in renal primary cilia to regulate a pathway important to kidney functional homeostasis. Autosomal dominant polycystic kidney disease (ADPKD) results when polycystin genes are mutated, but key cilia-based signaling pathways dysregulated by loss of polycystin function require elucidation. One cilia-dependent pathway suggested as playing a role in polycystic kidney diseases is the Hedgehog pathway, which is important in development, cancer, and ciliopathies. In mouse models of ADPKD, the authors used conditional control of gene expression to upregulate or inactivate Hedgehog in kidney cells that had undergone inactivation of Pkd1 , the gene encoding Polycystin-1. They found that the Hedgehog pathway had no significant effect on polycystic kidney disease initiated by Pkd1 inactivation, excluding it as a functional cell-autonomous component of kidney cyst formation in these ADPKD models. Background PKD1 or PKD2 , the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known. Methods To examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1 , we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity. Results We found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD. Conclusions These data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.