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Autosomal dominant polycystic kidney disease (ADPKD)

ADPKD is the most common human genetic disease. Despite the cloning of the two major disease genes, Pkd1 and Pkd2, the molecular and cellular basis of ADPKD remains unknown. We modeled autosomal dominant polycystic kidney disease mutations in zebrafish and made the unexpected finding that Polycystins modulate extracellular matrix synthesis, a long-ignored aspect of ADPKD but consistent with ADPKD-associated pathology including vascular aneurysm. Further, we showed that the defect is post-transcriptional, affecting the rate of translation or secretion of matrix collagen and involving COPII proteins. Finally we have shown that small molecule inhibitors of ER-Golgi traffic (brefeldin) rescue ADPKD pathology in zebrafish. Our work suggests that targeting COPII complexes and restoring secretory protein synthesis to normal levels is a new target pathway in the treatment of Autosomal Dominant Polycystic Kidney Disease.