Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction.

Abstract

Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis.

• Authors: Veronika Skuginna, Maciej Lech, Ramanjaneyulu Allam, Mi Ryu, Sebastian Clauss, Heni Eka Susanti, Christoph Römmele, Cecilia Garlanda, Alberto Mantovani, Hans-Joachim Anders
• Journal: PloS one (PLoS One) Vol. 6 Issue 4 Pg. e19204 (Apr 22 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21544241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Receptors, Interleukin-1
• Tir8 protein, mouse
• Tlr2 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 9
• Toll-Like Receptors

Topics

• Animals
• Fibrosis (genetics, metabolism)
• Kidney (pathology)
• Kidney Diseases (genetics, metabolism)
• Mice
• Mice, Mutant Strains
• Myeloid Differentiation Factor 88 (metabolism)
• Receptors, Interleukin-1 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics, physiology)
• Toll-Like Receptor 2 (genetics, metabolism)
• Toll-Like Receptor 9 (genetics, metabolism)
• Toll-Like Receptors (genetics, metabolism)
• Ureteral Obstruction (genetics, metabolism)