Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI

Shrikant Ramesh Mulay, Mohsen M. Honarpisheh, Orestes Foresto-Neto, Chongxu Shi, Jyaysi Desai, Zhi Bo Zhao, Julian A. Marschner, Bastian Popper, Ewa Miriam Buhl, Peter Boor, Andreas Linkermann, Helen Liapis, Rostyslav Bilyy, Martin Herrmann, Paola Romagnani, Ilya Belevich, Eija Jokitalo, Jan U. Becker, Hans-Joachim Anders

Research output: Contribution to journalArticleScientificpeer-review

Abstract

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.
Original languageEnglish
JournalJournal of the American Society of Nephrology
Volume30
Issue number10
Pages (from-to)1857-1869
ISSN1046-6673
DOIs
Publication statusPublished - Oct 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3121 Internal medicine

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