title: ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; beckm@musc.edu.
authors.forename: Monika
authors.initials: M
authors.lastname: Beck Gooz
authors.affiliation: Department of Drug Discovery and Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Maldonado
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Yujing
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: May Y
authors.initials: MY
authors.lastname: Amria
authors.affiliation: Department of Biochemistry and Molecular Genetics, Ehime University, Ehime, Japan;
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.affiliation: Department of Nephrology, University of Texas Health Science Center, San Antonio, Texas;
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.affiliation: Department of Drug Discovery and Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.affiliation: Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina.
authors.forename: P Darwin
authors.initials: PD
authors.lastname: Bell
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006019:Glycolysis / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016211:Transforming Growth Factor alpha / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D009025:Morpholines; C490898:Tg737Rpw protein, mouse; D016211:Transforming Growth Factor alpha; D025521:Tumor Suppressor Proteins; C484302:apratastat; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: ADAM17; ERK; cell proliferation; glycolysis; polycystic kidney disease (PKD)