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

Abstract

<i>PKD1</i> or <i>PKD2</i>, 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. To examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation <i>in vivo</i> in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of <i>Pkd1</i> combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in <i>Pkd1</i> initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of <i>Pkd1</i>, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity. We found that in <i>Pkd1</i> 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. These data suggest that loss of <i>Pkd1</i> function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.