The lonidamine derivative H2-gamendazole reduces cyst formation in polycystic kidney disease

Shirin V. Sundar, Julie Xia Zhou, Brenda S. Magenheimer, Gail A. Reif, Darren P. Wallace, Gunda I. Georg, Sudhakar R. Jakkaraj, Joseph S. Tash, Alan S.L. Yu, Xiaogang Li, James P. Calvet

Research output: Contribution to journalArticlepeer-review

Abstract

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-GMZtreated 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 Pkd1flox/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.

Original languageEnglish (US)
Pages (from-to)F492-F506
JournalAmerican Journal of Physiology - Renal Physiology
Volume323
Issue number4
DOIs
StatePublished - Oct 2022

Keywords

  • actin cytoskeleton
  • autosomal dominant polycystic kidney disease
  • cell motility
  • cell proliferation
  • cystic fibrosis transmembrane conductance regulator
  • fluid secretion
  • heat shock protein 90
  • metanephric organ culture

ASJC Scopus subject areas

  • Physiology
  • Urology

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