Shh Signaling Pathway In ADPKD

Abstract:Autosomal Dominant Polycystic Kidney Disease(ADPKD) is one of the most common monogenic diseases in the kidneys and is characterized by numerious fluid-filled renal cysts. ADPKD is caused by mutations in either PKD1or PKD2genes. Both genes encode two proteins which are named by polycystin-1(PCI) and polycystin-2(PC2), respectively. Recent studies indicate that PCI and PC2are able to form a protein complex via their COOH-terminal interaction and regulate several common cell signaling pathways, such as cAMP、mTOR、Wnt、Shh etc. Loss of either polycystins can dysregulate the signal pathways and leads aberrant ionic transportation, polarity, proliferation and apoptosis in the renal epitherlial cells, eventually result in renal cyst formation. Since Shh protein has been demonstrated to be closely associated with cilia in epithelial cell, we hypothesized that both polycystins and Shh may have epistatic function reciprocally and regulate cyst formation in ADPKD. To this end, we employed mutant mice in Pkd2and Shh to reveal the functional relationship between PC2and Shh in vivo.In this study, we have crossed the heterozygous Shh mice and the Pkd2conditional knockout mice to generate compound Shh::Pkd2deficient mice. Our finding suggests hypogenic Shh gene expression can not rescue the lethal phenotype and reduce renal cystic serverity, but it seems to improve the BUN and creatinine in ADPKD mouse model.In addition, we have also investigated PC2-lossing effects in Shh mutant mice. Interestinngly, we found that the lack of PC2increases the incidence of solitary kidney (from8.8%to20.6%). The results from the study indicate that downregulation of Shh may have a protective role for ADPKD and loss of PC2also impedes normal kidney development.