The purinergic 2X7 receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation

J Pathol. 2013 Nov;231(3):342-53. doi: 10.1002/path.4237. Epub 2013 Sep 3.


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.

Keywords: NLRP3; P2X7 receptor; metabolic syndrome; renal disease; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • Diabetic Nephropathies / immunology
  • Diabetic Nephropathies / metabolism
  • Diet, High-Fat*
  • Disease Models, Animal
  • Fibrosis
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Kidney / immunology
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / immunology
  • Metabolic Syndrome / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nephritis / etiology
  • Nephritis / immunology
  • Nephritis / metabolism*
  • Nephritis / pathology
  • Oxidative Stress
  • Podocytes / immunology
  • Podocytes / metabolism
  • Protein Carbonylation
  • Protein Processing, Post-Translational
  • RNA Interference
  • Receptors, Purinergic P2X7 / deficiency
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / metabolism*
  • Transfection


  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • PYCARD protein, human
  • Pycard protein, mouse
  • Receptors, Purinergic P2X7
  • Caspase 1