Molecular Pathogenesis and New Treatments of Polycystic Kidney Disease---The Role of Inflammation and Extracellular Matrix

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. It accounts for 1 in 1000 people in the general population. Thousands of cysts develop in the kidneys and the normal renal structure is distorted. Progression of ADPKD results in end-stage renal disease that requires maintenance dialysis or transplantation. Mutation of PKD genes causes abnormal polycystins which are critical for renal epithelial cells to maintain their functions. Abnormal cell proliferation and fluid secretion lead to cyst formation and enlargement. Current therapeutic strategies are largely targeting at proliferation and fluid secretion, but the results are only partially effective. Abnormalities in extracellular matrix and inflammatory reaction are two other possible disease mechanisms of ADPKD. Primary defects in extracellular matrix composition can cause cyst formation, while inflammation may accelerate disease progression. Extracellular matrix and inflammation are abnormally regulated in zebrafish models of ADPKD. We will investigate the role of inflammation and extracellular matrix in PKD pathogenesis, using different zebrafish cystic models and a transgenic zebrafish line (wt1b-eGFP) with pronephros-specific GFP expression. We will verify the effects of different compounds such as A438079, metformin, curcumin and celastrol that could inhibit extracellular matrix and inflammation in the novel Pkd1 microRNA knockdown mice. Molecular mechanisms of these effects will be elucidated. To extend the results, we will collect blood and urine samples of ADPKD patients. Biomarkers including CD14, MMP9, and IL-6 will be examined by ELISA. MicroRNAs will be examined by RT-PCR. We will examine if these biomarkers are elevated in ADPKD patients compared to control patients. Their possible association to annual decline of GFR and other clinical parameters (albuminuria, hypertension, infection and hematuria) will be explored. The study will help to elucidate the disease mechanism of ADPKD and identify new candidate biomarkers. The results will also contribute substantially to the treatment of ADPKD patients.

Project ID:PC10301-0549
External Project ID:NSC102-2314-B182A-120-MY2