Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy
| Autor: | Berend Isermann, Peter P. Nawroth, Satish Ranjan, Peter Söderkvist, Hongjie Wang, Herman Josef Gröne, Fabian Bock, Khurrum Shahzad, Sascha Pahernik, Vedat Schwenger, Stoyan Stoyanov, Christian Wacker, Klaus G. Reymann, Shrey Kohli, Stefan Kopf, Wei Dong, Moh'd Mohanad Al-Dabet, Olaf Groß, Juliane Wolter, Thati Madhusudhan, Ronald Biemann |
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| Rok vydání: | 2015 |
| Předmět: |
Mitochondrial ROS
Nlrp3 podocyte Inflammasomes immunology [Endothelial Cells] Kidney Glomerulus Inflammation mitochondrial ROS Severity of Illness Index Nephropathy Podocyte Diabetic nephropathy chemistry.chemical_compound Mice inflammasome NLR Family Pyrin Domain-Containing 3 Protein NLRP3 protein human medicine Animals Humans Diabetic Nephropathies ddc:610 immunology [Carrier Proteins] immunology [Podocytes] immunology [Diabetic Nephropathies] diabetic nephropathy endothelial cell business.industry Podocytes Klinisk medicin Endothelial Cells Inflammasome cytology [Kidney Glomerulus] medicine.disease immunology [Inflammasomes] Transplantation medicine.anatomical_structure chemistry Nephrology Immunology Cancer research Advanced glycation end-product medicine.symptom Clinical Medicine business Carrier Proteins medicine.drug |
| Zdroj: | Kidney international 87(1), 74-84 (2015). doi:10.1038/ki.2014.271 |
| ISSN: | 0085-2538 |
| DOI: | 10.1038/ki.2014.271 |
| Popis: | 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. Funding Agencies|Deutsche Forschungsgemeinschaft [IS 67/2-4, TH 1789/1-1, BI 1281/3-1]; EFSD (European Foundation for the Study of Diabetes); DDS (Deutsche Diabetes Stiftung); Hopp Stiftung; Stiftung fur Pathobiochemie und Molekulare Diagnostik; ERC StG; BioSysNet Research group |
| Databáze: | OpenAIRE |
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