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

Am J Physiol Renal Physiol. 2022 Oct 1;323(4):F492-F506. doi: 10.1152/ajprenal.00095.2022. Epub 2022 Aug 18.

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-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 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.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.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • Carboxylic Acids / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Cysts* / metabolism
  • EGF Family of Proteins / metabolism
  • Heat-Shock Proteins / metabolism
  • Humans
  • Indazoles / metabolism
  • Indazoles / pharmacology
  • Kidney / metabolism
  • Mice
  • Polycystic Kidney Diseases* / drug therapy
  • Polycystic Kidney Diseases* / metabolism
  • Polycystic Kidney, Autosomal Dominant* / drug therapy
  • Polycystic Kidney, Autosomal Dominant* / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Cell Surface

Substances

  • Actins
  • Carboxylic Acids
  • EGF Family of Proteins
  • Heat-Shock Proteins
  • Indazoles
  • Pkhd1 protein, mouse
  • Receptors, Cell Surface
  • gamendazole
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Colforsin
  • Proto-Oncogene Proteins c-akt
  • Cyclin-Dependent Kinase 4
  • lonidamine

Associated data

  • figshare/10.6084/m9.figshare.20371803