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The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.

Leemans JC, Butter LM, Pulskens WP, Teske GJ, Claessen N, van der Poll T, Florquin S - PLoS ONE (2009)

Bottom Line: We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury.Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals.Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.c.leemans@amc.uva.nl

ABSTRACT
Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2(-/-) or TLR2(+/+) mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals. Although, the obstructed kidneys of TLR2(-/-) mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

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Total and active TGF-β levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys.The amount of total TGFβ and activated TGFβ was significantly lower in kidneys from TLR2−/− mice compared to TLR2−/− mice 7 days after UUO-induced injury. Data are mean and SEM of six mice per group. *p<0.05.
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pone-0005704-g009: Total and active TGF-β levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys.The amount of total TGFβ and activated TGFβ was significantly lower in kidneys from TLR2−/− mice compared to TLR2−/− mice 7 days after UUO-induced injury. Data are mean and SEM of six mice per group. *p<0.05.

Mentions: TGFβ is one of the most important molecules in the pathogenesis of renal fibrogenesis [29]. To determine whether the reduction in renal fibrosis and apoptosis in TLR2−/− mice was associated with an alteration in TGFβ, we finally examined TGFβ protein. This revealed that the amount of total TGFβ as well as activated TGFβ was significantly lower in kidneys from TLR2−/− mice compared to TLR2+/+ mice 7 days after UUO-induced injury (Fig. 9). A trend towards less (active) TGFβ was furthermore seen 14 days after UUO-induced injury (not significant). As HGF antagonizes the fibrogenic effects of TGFβ, we also analyzed the renal level of this growth factor and found no significant differences between TLR2+/+ and TLR2−/− mice at all time points (data not shown).


The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury.

Leemans JC, Butter LM, Pulskens WP, Teske GJ, Claessen N, van der Poll T, Florquin S - PLoS ONE (2009)

Total and active TGF-β levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys.The amount of total TGFβ and activated TGFβ was significantly lower in kidneys from TLR2−/− mice compared to TLR2−/− mice 7 days after UUO-induced injury. Data are mean and SEM of six mice per group. *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682651&req=5

pone-0005704-g009: Total and active TGF-β levels in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral non-obstructed kidneys.The amount of total TGFβ and activated TGFβ was significantly lower in kidneys from TLR2−/− mice compared to TLR2−/− mice 7 days after UUO-induced injury. Data are mean and SEM of six mice per group. *p<0.05.
Mentions: TGFβ is one of the most important molecules in the pathogenesis of renal fibrogenesis [29]. To determine whether the reduction in renal fibrosis and apoptosis in TLR2−/− mice was associated with an alteration in TGFβ, we finally examined TGFβ protein. This revealed that the amount of total TGFβ as well as activated TGFβ was significantly lower in kidneys from TLR2−/− mice compared to TLR2+/+ mice 7 days after UUO-induced injury (Fig. 9). A trend towards less (active) TGFβ was furthermore seen 14 days after UUO-induced injury (not significant). As HGF antagonizes the fibrogenic effects of TGFβ, we also analyzed the renal level of this growth factor and found no significant differences between TLR2+/+ and TLR2−/− mice at all time points (data not shown).

Bottom Line: We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury.Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals.Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.c.leemans@amc.uva.nl

ABSTRACT
Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2(-/-) or TLR2(+/+) mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-beta in kidneys of TLR2(-/-) mice compared with TLR2(+/+) animals. Although, the obstructed kidneys of TLR2(-/-) mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

Show MeSH
Related in: MedlinePlus