title: Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy.
abstract: Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.
authors: 1] Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany [2] University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan.
authors: Khurrum
authors: K
authors: Shahzad
authors: 1] Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany [2] Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors: Fabian
authors: F
authors: Bock
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Wei
authors: W
authors: Dong
authors: 1] Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany [2] Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Hongjie
authors: H
authors: Wang
authors: Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors: Stefan
authors: S
authors: Kopf
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Shrey
authors: S
authors: Kohli
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Moh'd Mohanad
authors: MM
authors: Al-Dabet
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Satish
authors: S
authors: Ranjan
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Juliane
authors: J
authors: Wolter
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Christian
authors: C
authors: Wacker
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Ronald
authors: R
authors: Biemann
authors: German Centre for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors: Stoyan
authors: S
authors: Stoyanov
authors: German Centre for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors: Klaus
authors: K
authors: Reymann
authors: Faculty of Health Sciences, Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors: Peter
authors: P
authors: Söderkvist
authors: Institut für Klinische Chemie und Pathobiochemie, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors: Olaf
authors: O
authors: Groß
authors: Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
authors: Vedat
authors: V
authors: Schwenger
authors: 1] Department of Urology, University of Heidelberg, Heidelberg, Germany [2] Tissue Bank of the National Center for Tumor Disease, University of Heidelberg, Heidelberg, Germany.
authors: Sascha
authors: S
authors: Pahernik
authors: Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors: Peter P
authors: PP
authors: Nawroth
authors: German Cancer Research Center, Department of Cellular and Molecular Pathology, Heidelberg, Germany.
authors: Herman-Josef
authors: HJ
authors: Gröne
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Thati
authors: T
authors: Madhusudhan
authors: Department of Clinical Chemistry and Pathobiochemistry, Institute of Clinical Pathology and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Berend
authors: B
authors: Isermann
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D003928:Diabetic Nephropathies / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D007678:Kidney Glomerulus / Q000166:cytology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D050199:Podocytes / Q000276:immunology; D012720:Severity of Illness Index
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human