Universität zu Köln

Mulay, Shrikant Ramesh, Honarpisheh, Mohsen M., Foresto-Neto, Orestes ORCID: 0000-0001-7548-4327, Shi, Chongxu, Desai, Jyaysi, Zhao, Zhi Bo, Marschner, Julian A., Popper, Bastian, Buhl, Ewa Miriam, Boor, Peter, Linkermann, Andreas ORCID: 0000-0001-6287-9725, Liapis, Helen, Bilyy, Rostyslav ORCID: 0000-0002-2344-1349, Herrmann, Martin ORCID: 0000-0002-0258-2484, Romagnani, Paola ORCID: 0000-0002-1774-8088, Belevich, Ilya ORCID: 0000-0003-2190-4909, Jokitalo, Eija ORCID: 0000-0002-4159-6934, Becker, Jan U. and Anders, Hans-Joachim (2019). Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI. J. Am. Soc. Nephrol., 30 (10). S. 1857 - 1870. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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) inflamma-some 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 MIkI 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mulay, Shrikant Ramesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Honarpisheh, Mohsen M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Foresto-Neto, Orestes UNSPECIFIED orcid.org/0000-0001-7548-4327 UNSPECIFIED Shi, Chongxu UNSPECIFIED UNSPECIFIED UNSPECIFIED Desai, Jyaysi UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Zhi Bo UNSPECIFIED UNSPECIFIED UNSPECIFIED Marschner, Julian A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Popper, Bastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Buhl, Ewa Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Boor, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Linkermann, Andreas UNSPECIFIED orcid.org/0000-0001-6287-9725 UNSPECIFIED Liapis, Helen UNSPECIFIED UNSPECIFIED UNSPECIFIED Bilyy, Rostyslav UNSPECIFIED orcid.org/0000-0002-2344-1349 UNSPECIFIED Herrmann, Martin UNSPECIFIED orcid.org/0000-0002-0258-2484 UNSPECIFIED Romagnani, Paola UNSPECIFIED orcid.org/0000-0002-1774-8088 UNSPECIFIED Belevich, Ilya UNSPECIFIED orcid.org/0000-0003-2190-4909 UNSPECIFIED Jokitalo, Eija UNSPECIFIED orcid.org/0000-0002-4159-6934 UNSPECIFIED Becker, Jan U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Anders, Hans-Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-132075
DOI:	10.1681/ASN.2018121218
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	30
Number:	10
Page Range:	S. 1857 - 1870
Date:	2019
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYCLOPHILIN-D; CELL-DEATH; RENAL-FAILURE; CRYSTALS; ACTIVATION; MECHANISMS Multiple languages Urology & Nephrology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13207