title: The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation.
abstract: Renal disease associated with type 2 diabetes and the metabolic syndrome is characterized by a distinct inflammatory phenotype. The purinergic 2X7 receptor (P2X7 R) and the nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasome have been separately shown to play a role in two models of non-metabolic chronic kidney disease. Moreover, the NLRP3 inflammasome has been implicated in chronic low-grade sterile inflammation characterizing metabolic disorders, though the mechanism(s) involved in inflammasome activation under these conditions are still unknown. We investigated the role of P2X7 R (through activation of the NLRP3 inflammasome) in renal inflammation and injury induced by a high-fat diet, an established model of the metabolic syndrome. On a high-fat diet, mice lacking P2X7 R developed attenuated renal functional and structural alterations as well as reduced inflammation, fibrosis, and oxidative/carbonyl stress, as compared with wild-type animals, in the absence of significant differences in metabolic parameters. This was associated with blunted up-regulation of the NLRP3 inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase 1, pro-interleukin (IL)-1β, and pro-IL-18, as well as reduced inflammasome activation, as evidenced by decreased formation of mature caspase 1, whereas mature IL-1β and IL-18 were not detected. Up-regulated expression of NLRP3 and pro-caspase 1, post-translational processing of pro-caspase-1, and release of IL-18 in response to lipopolysaccharide + 2'(3')-O-(4-benzoylbenzoyl)ATP were attenuated by P2X7 R silencing in cultured mouse podocytes. Protein and mRNA expression of P2X7 R, NLRP3, and ASC were also increased in kidneys from subjects with type 2 diabetes and the metabolic syndrome, showing histologically documented renal disease. These data provide evidence of a major role for the purinergic system, at least in part through activation of the NLRP3 inflammasome, in the process driving 'metabolic' renal inflammation and injury and identify P2X7 R and NLRP3 as novel therapeutic targets.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Solini
authors.forename: Stefano
authors.initials: S
authors.lastname: Menini
authors.forename: Chiara
authors.initials: C
authors.lastname: Rossi
authors.forename: Carlo
authors.initials: C
authors.lastname: Ricci
authors.forename: Eleonora
authors.initials: E
authors.lastname: Santini
authors.forename: Claudia
authors.initials: C
authors.lastname: Blasetti Fantauzzi
authors.forename: Carla
authors.initials: C
authors.lastname: Iacobini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000276:immunology / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005355:Fibrosis; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009393:Nephritis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D050199:Podocytes / Q000276:immunology / Q000378:metabolism; D050050:Protein Carbonylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C402202:PYCARD protein, human; C498534:Pycard protein, mouse; D058486:Receptors, Purinergic P2X7; D020170:Caspase 1
keywords: NLRP3; P2X7 receptor; metabolic syndrome; renal disease; type 2 diabetes