Downregulation of Notch Signaling Pathway Decreases Primary Cilium Lengths in Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) affects over half a million people and causes around 10% of end stage renal failure in the United States. One of the most prominent symptoms of ADPKD includes the presence of renal cysts that over time, interfere with kidney function. The cause of ADPKD consists of genetic mutations in the PKD1 and PKD2 genes. These mutations negatively influence the formation in polycystin1 and polycystin2 protein complex (PC1 and PC2 protein complex) which regulates intracellular and extracellular calcium flow in the primary cilium. An intracellular loss of calcium has been shown to be correlated with cell proliferation. Previous research has also established a connection between Cux1, a murine homolog of Cut from drosophila melanogaster, and cell proliferation in kidneys of affected patients. Additionally, a relationship between Cux1 and Notch1, a receptor of the Notch signaling pathway, has also been detected. It was discovered that Notch1 upregulated Cux1 indicating that the Notch signaling pathway is involved in cyst formation in ADPKD. This present study looked at the Notch signaling pathway and its relation to cyst formation. In this study, primary cilium lengths were compared with those of Recombination Signal Binding Protein for Immunoglobin Kappa J (RBPj) knockout mice. Knocking out RBPj inhibits the Notch pathway as it is a crucial part of the signaling pathway. This study, through immunofluorescence discovered that there was a significant difference in the cilia lengths between wild type and Notch inhibited mice. These findings suggest that there are new possible therapeutic treatments for ADPKD by inhibiting the Notch signaling pathway.