Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney Disease

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) causes severe disease in babies in the womb. Those who survive the neonatal period face chronic kidney and liver disease throughout their life. The overall goal of our study was to uncover therapeutic strategies to treat ARPKD. BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD)Q5 is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). Severe disease occurs in perinates. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here was to uncover therapeutic strategies for ARPKD. METHODS:We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using Western blotting and protein trafficking using confocal microscopy. RESULTS:We found that the protein level of the cystic fibrosis transmembrane conductance regulator (CFTR) was downregulated. The levels of heat shock proteins (HSPs) were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90 and HSP70 upregulated. FPCmutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through messenger RNA inhibition, or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing HSP27 or inhibiting HSP70 or HSP90 restored CFTR localization toward normal values.CONCLUSIONS: FPC malfunction induces the formation of cysts, which are fueled by alterations in HSPs and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

“…On the other hand, mice with a double knockout ( bpk −/− ; cftr −/− ) exhibited greatly enlarged kidneys and died earlier than cystic control mice. In the recent work on Pkhd1 del4/del4 cholangiocytes from ARPKD mice, which display progressive liver and pancreatic cyst formation, CFTR was found to be down-regulated [ 46 ]. Forskolin-induced cyst growth was reduced in these cells by CFTR Corrector VX-809, as well as by heat shock proteins (HSPs; by increasing HSP27 or reducing HSP90 or HSP70).…”