Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis

PLoS One. 2011;6(12):e29004. doi: 10.1371/journal.pone.0029004. Epub 2011 Dec 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / administration & dosage
  • Adenine / pharmacology
  • Allopurinol / pharmacology
  • Allopurinol / therapeutic use
  • Animals
  • Diet
  • Disease Progression
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Inflammation / pathology
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology*
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism*
  • Nephritis, Interstitial / drug therapy
  • Nephritis, Interstitial / metabolism*
  • Nephritis, Interstitial / pathology*
  • Nephritis, Interstitial / prevention & control
  • Signal Transduction / drug effects
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • Xanthine Dehydrogenase / antagonists & inhibitors
  • Xanthine Dehydrogenase / metabolism

Substances

  • Inflammasomes
  • Myeloid Differentiation Factor 88
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Allopurinol
  • Xanthine Dehydrogenase
  • Adenine