Downregulation of Cux1 Increases Cilia Length and Decreases Oral-Facial-Digital Type 1 Protein Expression in Polycystic Kidney Disease
Wee, Zhi Nee
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Polycystic kidney disease (PKD) is a form of chronic kidney disease (CKD) in which fluid-filled cysts form in the kidneys, resulting in life-threatening complications and renal failure. PKD can be inherited in two forms—autosomal recessive polycystic kidney disease (ARPKD) or autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common kidney diseases, with mutations in PKD1 and PKD2 as the leading cause of the disease. Polycystin-1 (PC1) and polycystin-2 (PC2), encoded by PKD1 and PKD2 respectively, are found on the membrane of the primary cilia; they were thought to detect fluid flow in the renal tubules, regulating intracellular calcium levels and thus, kidney tubule development. A regulator of cell growth in kidney development and polycystic kidney disease is the transcription factor Cux1. Recent studies have implicated Cux1 in the regulation of several cilia genes, one being OFD1 (oral-facial-digital type 1), which causes CKD when mutated. In this study, cilia length and OFD1 expression of several mouse models of Cux1 and polycystic kidney disease were measured through double immunofluorescence labeling of alpha-tubulin and OFD1. We found that decreased expression of Cux1, either alone, or combined with Pkd1 mutations, resulted in increased cilia length and decreased OFD1 expression. These findings support a role for Cux1 in regulating ciliary development and function, suggesting another mechanism in which Cux1 may be involved in PKD, which may lead to new therapeutic targets for treatment of ADPKD.