| First Author | Yanda MK | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 29 | Pages | 11513-11526 |
| PubMed ID | 29875161 | Mgi Jnum | J:267093 |
| Mgi Id | MGI:6197327 | Doi | 10.1074/jbc.RA118.001846 |
| Citation | Yanda MK, et al. (2018) A potential strategy for reducing cysts in autosomal dominant polycystic kidney disease with a CFTR corrector. J Biol Chem 293(29):11513-11526 |
| abstractText | Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of cysts, leading to a decline in function and renal failure that cannot be prevented by current treatments. Mutations in pkd1 and pkd2, encoding the polycystin 1 and 2 proteins, induce growth-related pathways, including heat shock proteins, as occurs in some cancers, raising the prospect that pharmacological interventions that target these pathways might alleviate or prevent ADPKD. Here, we demonstrate a role for VX-809, a corrector of cystic fibrosis transmembrane conductance regulator (CFTR), conventionally used to manage cystic fibrosis in reducing renal cyst growth. VX-809 reduced cyst growth in Pkd1-knockout mice and in proximal, tubule-derived, cultured Pkd1 knockout cells. VX-809 reduced both basal and forskolin-activated cAMP levels and also decreased the expression of the adenylyl cyclase AC3 but not of AC6. VX-809 also decreased resting levels of intracellular Ca(2+) but did not affect ATP-stimulated Ca(2+) release. Notably, VX-809 dramatically decreased thapsigargin-induced release of Ca(2+) from the endoplasmic reticulum (ER). VX-809 also reduced the levels of heat shock proteins Hsp27, Hsp70, and Hsp90 in mice cystic kidneys, consistent with the restoration of cellular proteostasis. Moreover, VX-809 strongly decreased an ER stress marker, the GADD153 protein, and cell proliferation but had only a small effect on apoptosis. Given that administration of VX-809 is safe, this drug potentially offers a new way to treat patients with ADPKD. |
