Shrikant Ramesh Mulay1,2, Mohsen M Honarpisheh3, Orestes Foresto-Neto3, Chongxu Shi3, Jyaysi Desai3, Zhi Bo Zhao3, Julian A Marschner3, Bastian Popper4, Ewa Miriam Buhl5, Peter Boor5, Andreas Linkermann6, Helen Liapis7,8, Rostyslav Bilyy9, Martin Herrmann10, Paola Romagnani11, Ilya Belevich12, Eija Jokitalo12, Jan U Becker13, Hans-Joachim Anders1. 1. Division of Nephrology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany; shrikant.mulay@cdri.res.in hjanders@med.uni-muenchen.de. 2. Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India. 3. Division of Nephrology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany. 4. Biomedical Center, Core Facility Animal Models, Ludwig Maximilian University, Planegg-Martinsried, Germany. 5. Division of Nephrology, Institute of Pathology, Rheinisch-Westfälische Technische Hochschule University of Aachen, Aachen, Germany. 6. Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany. 7. Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri. 8. Arkana Laboratories, Little Rock, Arkansas. 9. Department of Histology, Cytology, and Embryology, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine. 10. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany. 11. Excellence Centre for Research, Transfer and High Education for the Development of De Novo Therapies, University of Florence, Florence, Italy. 12. Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland; and. 13. Institute of Pathology, University of Cologne, Cologne, Germany.
Abstract
BACKGROUND: Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function. METHODS: To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted in vitro studies in mouse and human kidney cells and in vivo studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl. RESULTS: Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF-dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of Ppif and Mlkl or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI. CONCLUSIONS: Mitochondrial permeability transition-related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.
BACKGROUND: Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycolpoisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function. METHODS: To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted in vitro studies in mouse and human kidney cells and in vivo studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl. RESULTS: Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF-dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of Ppif and Mlkl or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI. CONCLUSIONS: Mitochondrial permeability transition-related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.
Authors: Stephen W G Tait; Andrew Oberst; Giovanni Quarato; Sandra Milasta; Martina Haller; Ruoning Wang; Maria Karvela; Gabriel Ichim; Nader Yatim; Matthew L Albert; Grahame Kidd; Randall Wakefield; Sharon Frase; Stefan Krautwald; Andreas Linkermann; Douglas R Green Journal: Cell Rep Date: 2013-11-21 Impact factor: 9.423
Authors: Shrikant R Mulay; Jyaysi Desai; Santhosh V Kumar; Jonathan N Eberhard; Dana Thomasova; Simone Romoli; Melissa Grigorescu; Onkar P Kulkarni; Bastian Popper; Volker Vielhauer; Gabriele Zuchtriegel; Christoph Reichel; Jan Hinrich Bräsen; Paola Romagnani; Rostyslav Bilyy; Luis E Munoz; Martin Herrmann; Helen Liapis; Stefan Krautwald; Andreas Linkermann; Hans-Joachim Anders Journal: Nat Commun Date: 2016-01-28 Impact factor: 14.919
Authors: Holger Scholz; Felix J Boivin; Kai M Schmidt-Ott; Sebastian Bachmann; Kai-Uwe Eckardt; Ute I Scholl; Pontus B Persson Journal: Nat Rev Nephrol Date: 2021-02-05 Impact factor: 28.314
Authors: Michael T Collins; Gemma Marcucci; Hans-Joachim Anders; Giovanni Beltrami; Jane A Cauley; Peter R Ebeling; Rajiv Kumar; Agnès Linglart; Luca Sangiorgi; Dwight A Towler; Ria Weston; Michael P Whyte; Maria Luisa Brandi; Bart Clarke; Rajesh V Thakker Journal: Nat Rev Endocrinol Date: 2022-05-16 Impact factor: 47.564
Authors: Wulf Tonnus; Claudia Meyer; Christian Steinebach; Alexia Belavgeni; Anne von Mässenhausen; Nadia Zamora Gonzalez; Francesca Maremonti; Florian Gembardt; Nina Himmerkus; Markus Latk; Sophie Locke; Julian Marschner; Wenjun Li; Spencer Short; Sebastian Doll; Irina Ingold; Bettina Proneth; Christoph Daniel; Nazanin Kabgani; Rafael Kramann; Stephen Motika; Paul J Hergenrother; Stefan R Bornstein; Christian Hugo; Jan Ulrich Becker; Kerstin Amann; Hans-Joachim Anders; Daniel Kreisel; Derek Pratt; Michael Gütschow; Marcus Conrad; Andreas Linkermann Journal: Nat Commun Date: 2021-07-20 Impact factor: 14.919