The lonidamine derivative H2-gamendazole reduces cyst formation in polycystic kidney disease
| Autor: | Brenda S. Magenheimer, Joseph S. Tash, Xiaogang Li, Darren P. Wallace, Sudhakar Jakkaraj, Shirin V. Sundar, Gail A. Reif, Gunda I. Georg, James P. Calvet, Xia Zhou, Alan S.L. Yu |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
medicine.medical_specialty
EGF Family of Proteins Indazoles Physiology Autosomal dominant polycystic kidney disease Carboxylic Acids Motility Cystic Fibrosis Transmembrane Conductance Regulator Receptors Cell Surface Kidney chemistry.chemical_compound Mice Internal medicine medicine Polycystic kidney disease Animals Humans Cyst Cells Cultured Heat-Shock Proteins Cell Proliferation Polycystic Kidney Diseases Cell growth Cysts Colforsin Lonidamine Gamendazole Cyclin-Dependent Kinase 4 medicine.disease Actin cytoskeleton Polycystic Kidney Autosomal Dominant Actins Endocrinology chemistry Proto-Oncogene Proteins c-akt |
| Zdroj: | American Journal of Physiology-Renal Physiology. 323:F492-F506 |
| ISSN: | 1522-1466 1931-857X |
| DOI: | 10.1152/ajprenal.00095.2022 |
| Popis: | 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 have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation usingin vitroandin vivomodels of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl−channel. 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. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement.In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in thePkd1flox/flox:Pkhd1-Cremouse 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. |
| Databáze: | OpenAIRE |
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