PHARMACEUTICAL COMPOSITION FOR TREATING AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE CONTAINING INTRAFLAGELLAR TRANSPORT 46 AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE ANIMAL MODEL

摘要

Primary cilla are finger-shaped structures assembled by intraflagellar transport and function as a sensor to mechanical and chemical signals. Deficiency of cilla relates with progress of polycystic kidney disease and determination of the mechanism of deficiency of cilla is very important in understanding polycystic kidney disease. According to the present invention, the function of IFT46 has been found in the kidney epithelial cells and mouse kidney. When IFT 46 is reduced, cilla are shortened and the path of MAPK is activated to increase the growth of cells in the kidney epithelial cells. In addition, a decrease in IFT46 expression affects the PC2 activity controlled by the flow sensing. An abnormal condition caused by a decrease in IFT46 expression induced rapid cysts in a 3D culture system. In fact, the level of IFT46 mRNA and protein is dramatically reduced in the cilla-deficient human polycystic kidney tissue as compared to the normal kidney. Based on such results, a mouse having specifically reduced IFT 46 in its kidney is made according to the present invention. Deficiency of IFT46 genes in the kidney induced a severe polycystic kidney phenotype lost with cilla and mTOR path activity. Such results suggest that abnormality of cilla caused by IFT46 deficiency functions as an etiological factor during the progress of polycystic kidney disease.