title: Effects of a human recombinant alkaline phosphatase during impaired mitochondrial function in human renal proximal tubule epithelial cells.
abstract: Sepsis-associated acute kidney injury is a multifactorial syndrome in which inflammation and renal microcirculatory dysfunction play a profound role. Subsequently, renal tubule mitochondria reprioritize cellular functions to prevent further damage. Here, we investigated the putative protective effects of human recombinant alkaline phosphatase (recAP) during inhibition of mitochondrial respiration in conditionally immortalized human proximal tubule epithelial cells (ciPTEC). Full inhibition of mitochondrial oxygen consumption was obtained after 24h antimycin A treatment, which did not affect cell viability. While recAP did not affect the antimycin A-induced decreased oxygen consumption and increased hypoxia-inducible factor-1α or adrenomedullin gene expression levels, the antimycin A-induced increase of pro-inflammatory cytokines IL-6 and IL-8 was attenuated. Antimycin A tended to induce the release of detrimental purines ATP and ADP, which reached statistical significance when antimycin A was co-incubated with lipopolysaccharide, and were completely converted into cytoprotective adenosine by recAP. As the adenosine A2Areceptor was up-regulated after antimycin A exposure, an adenosine A2Areceptor knockout ciPTEC cell line was generated in which recAP still provided protection. Together, recAP did not affect oxygen consumption but attenuated the inflammatory response during impaired mitochondrial function, an effect suggested to be mediated by dephosphorylating ATP and ADP into adenosine.
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Esther.Peters@radboudumc.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: Peters
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Mitochondrial Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Tom.Schirris@radboudumc.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: Schirris
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Sander.BaronvanAsbeck@radboudumc.nl.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: van Asbeck
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Jelle.Gerretsen@radboudumc.nl.
authors.forename: Jelle
authors.initials: J
authors.lastname: Gerretsen
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Jenny.Eymael@radboudumc.nl.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Eymael
authors.affiliation: Department of Neurology, Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Angel.Ashikov@radboudumc.nl.
authors.forename: Angel
authors.initials: A
authors.lastname: Ashikov
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Merel.Adjobo-Hermans@radboudumc.nl.
authors.forename: Merel J W
authors.initials: MJ
authors.lastname: Adjobo-Hermans
authors.affiliation: Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Mitochondrial Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Frans.Russel@radboudumc.nl.
authors.forename: Frans
authors.initials: F
authors.lastname: Russel
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, 6500 HB Nijmegen, The Netherlands. Electronic address: Peter.Pickkers@radboudumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO BOX 80082, 3508 TB Utrecht, The Netherlands. Electronic address: R.Masereeuw@uu.nl.
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000494:pharmacology*; D000968:Antimycin A / Q000494:pharmacology; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D000968:Antimycin A; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase
keywords: Adenosine; Antimycin A (PubChem CID: 16218979); Human recombinant alkaline phosphatase; Inflammation; Lipopolysaccharide (PubChem CID: 11970143); Mitochondria; Myxothiazol (PubChem CID: 6437357); Proximal tubule epithelial cells; Respiratory inhibition