| Autor: |
Sundar SV; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Zhou JX; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota., Magenheimer BS; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas., Reif GA; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas., Wallace DP; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas., Georg GI; Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota., Jakkaraj SR; Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota., Tash JS; Department of Molecular and Integrated Physiology, University of Kansas Medical Center, Kansas City, Kansas., Yu ASL; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas., Li X; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.; Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota., Calvet JP; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas.; Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas. |
| Abstrakt: |
Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl - secretion. We tested the effectiveness of the indazole carboxylic acid H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl - -mediated short-circuit currents in human ADPKD cells, and it significantly inhibited both cAMP- and epidermal growth factor-induced proliferation of ADPKD cells. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and decreased hyperphosphorylated retinoblastoma levels. H2-GMZ treatment also decreased ErbB2, Akt, and cyclin-dependent kinase 4, consistent with inhibition of heat shock protein 90, and it decreased levels of the cystic fibrosis transmembrane conductance regulator Cl - channel protein. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Experiments using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1 flox/flox : Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl - secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD. NEW & NOTEWORTHY Autosomal dominant polycystic kidney disease (ADPKD) is a renal neoplastic disorder characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl - secretion. This study shows that the lonidamine derivative H2-GMZ inhibits Cl - secretion, cell proliferation, and cyst growth, suggesting that it might have therapeutic value for the treatment of ADPKD. |
