ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease.

Academic Article

Abstract

  • Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst formation in the kidneys and other organs that ultimately results in kidney failure and death. Currently, there is no therapy for slowing down or stopping the progression of PKD. In this study, we identified the disintegrin metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney tissues of conditional knockout Ift88(-/-) mice and collecting duct epithelial cells from Ift88°(rpk) mice, animal models of autosomal recessive polycystic kidney disease (ARPKD). Using Western blotting, an enzyme activity assay, and a growth factor-shedding assay in the presence or absence of the specific ADAM17 inhibitor TMI-005, we show that increased expression and activation of ADAM17 in the cystic kidney and in collecting duct epithelial cells originating from the Ift88°(rpk) mice (designated as PKD cells) lead to constitutive shedding of several growth factors, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, and transforming growth factor-α (TGF-α). Increased growth factor shedding induces activation of the EGFR/MAPK/ERK pathway and maintains higher cell proliferation rate in PKD cells compared with control cells. PKD cells also displayed increased lactate formation and extracellular acidification indicative of aerobic glycolysis (Warburg effect), which was blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of cellular proliferation in PKD cells by activating the EGFR/ERK axis and a proproliferative glycolytic phenotype.
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    Keywords

  • ADAM17, ERK, cell proliferation, glycolysis, polycystic kidney disease (PKD), ADAM Proteins, ADAM17 Protein, Animals, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Epithelial Cells, ErbB Receptors, Extracellular Signal-Regulated MAP Kinases, Female, Glycolysis, Heparin-binding EGF-like Growth Factor, Kidney Tubules, Collecting, Male, Mice, Mice, Knockout, Morpholines, Phenotype, Polycystic Kidney Diseases, Transforming Growth Factor alpha, Tumor Suppressor Proteins
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    Author List

  • Beck Gooz M; Maldonado EN; Dang Y; Amria MY; Higashiyama S; Abboud HE; Lemasters JJ; Bell PD
  • Start Page

  • F551
  • End Page

  • F559
  • Volume

  • 307
  • Issue

  • 5