title: Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis.
abstract: Tubule-interstitial nephritis (TIN) results in decreased renal function and interstitial inflammation, which ultimately leads to fibrosis. Excessive adenine intake can cause TIN because xanthine dehydrogenase (XDH) can convert this purine into an insoluble compound, which precipitates in the tubuli. Innate immune sensors, such as Toll-like receptors (TLR) and inflammasome complex, play a crucial role in the initiation of inflammation. The aim of this study was to evaluate the roles of TLR-2 and -4, Myd88 and inflammasome complex in an experimental model of TIN. Here, we show that wild-type (WT) mice fed adenine-enriched food exhibited significant renal dysfunction and enhanced cellular infiltration accompanied by collagen deposition. They also presented higher gene and protein expression of pro-inflammatory cytokines. In contrast, TLR-2, -4, MyD88, ASC and Caspase-1 KO mice showed renoprotection associated with expression of inflammatory molecules at levels comparable to controls. Furthermore, treatment of WT animals with allopurinol, an XDH inhibitor, led to reduced levels of uric acid, oxidative stress, collagen deposition and a downregulation of the NF-kB signaling pathway. We concluded that MyD88 signaling and inflammasome participate in the development of TIN. Furthermore, inhibition of XDH seems to be a promising way to therapeutically target the developing inflammatory process.
authors.affiliation: Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
authors.forename: Matheus
authors.initials: M
authors.lastname: Correa-Costa
authors.forename: Tarcio Teodoro
authors.initials: TT
authors.lastname: Braga
authors.forename: Patricia
authors.initials: P
authors.lastname: Semedo
authors.forename: Caroline Yuri
authors.initials: CY
authors.lastname: Hayashida
authors.forename: Luiz Roberto Grassmann
authors.initials: LR
authors.lastname: Bechara
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Elias
authors.forename: Claudiene Rodrigues
authors.initials: CR
authors.lastname: Barreto
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva-Cunha
authors.forename: Meire Ioshie
authors.initials: MI
authors.lastname: Hyane
authors.forename: Giselle Martins
authors.initials: GM
authors.lastname: Gonçalves
authors.forename: Patricia Chakur
authors.initials: PC
authors.lastname: Brum
authors.forename: Clarice
authors.initials: C
authors.lastname: Fujihara
authors.forename: Roberto
authors.initials: R
authors.lastname: Zatz
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pacheco-Silva
authors.forename: Dario S
authors.initials: DS
authors.lastname: Zamboni
authors.forename: Niels Olsen Saraiva
authors.initials: NO
authors.lastname: Camara
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004032:Diet; D018450:Disease Progression; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000493:Allopurinol; D014968:Xanthine Dehydrogenase; D000225:Adenine