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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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Expression and localization of TLR2 in UUO-injured kidney of TLR2+/+ mice at several time points.The amount of TLR2 mRNA (A) and protein (B) was markedly upregulated after UUO injury. Data are mean and SEM of six mice per group; *p<0.05. High magnification images (inserts) show that 3 and 7 days after UUO TLR2 was mainly located at the apical side of renal tubules in both cortex and medulla. After 14 days, apical tubular TLR2 staining in cortex and medulla is lost and extended into the cytoplasm and the interstitium.
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pone-0005704-g002: Expression and localization of TLR2 in UUO-injured kidney of TLR2+/+ mice at several time points.The amount of TLR2 mRNA (A) and protein (B) was markedly upregulated after UUO injury. Data are mean and SEM of six mice per group; *p<0.05. High magnification images (inserts) show that 3 and 7 days after UUO TLR2 was mainly located at the apical side of renal tubules in both cortex and medulla. After 14 days, apical tubular TLR2 staining in cortex and medulla is lost and extended into the cytoplasm and the interstitium.

Mentions: To evaluate the influence of fibrinogenesis at different stages on the expression and localization of TLR2 we next measured the amount of mRNA and protein in UUO-injured kidney of TLR2+/+ mice at several time points. This revealed that the amount of TLR2 mRNA was almost 5 times increased 3 days after UUO and continued to increase at later time points (Fig. 2A). The expression pattern of TLR2 protein followed a similar trend as compared to TLR2 mRNA expression. TLR2 protein was markedly upregulated 3, 7 and 14 after UUO-injury in kidneys of TLR2+/+ mice as compared with the contralateral unobstructed kidneys (Fig. 2B). High magnification images (inserts) show that 3 and 7 days after the induction of injury TLR2 was predominantly located at the apical side of renal tubules. After 14 days, apical TLR2 staining seems to be lost and in stead extended into the cytoplasm and interstitium. Control sections (t = 14), omitting primary antibody showed no overt staining (data not shown). Analysis of the expression of known endogenous stress ligands that potentially could activate TLR2, e.g. Gp96, biglycan, HMGB1, HSP60 and HSP70 [16], [19], [26]–[28] during progressive renal injury revealed a strong upregulation of the amount of biglycan (t = 7, 14), HMGB1 (t = 14), and Gp96 (t = 14) mRNA after UUO injury compared to contralateral kidneys (Fig. 3A). In line, we found a profound upregulation of tubulointerstitial Gp96, tubular biglycan and HMGB1 protein 14 days after the induction of UUO injury (Figure 3B). No upregulation was seen in HSP70 and HSP60 mRNA levels after UUO-injury (data not shown). Together, these data suggest that progressive renal injury leads to a marked enhancement of TLR2 and several main endogenous stress ligands.


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)

Expression and localization of TLR2 in UUO-injured kidney of TLR2+/+ mice at several time points.The amount of TLR2 mRNA (A) and protein (B) was markedly upregulated after UUO injury. Data are mean and SEM of six mice per group; *p<0.05. High magnification images (inserts) show that 3 and 7 days after UUO TLR2 was mainly located at the apical side of renal tubules in both cortex and medulla. After 14 days, apical tubular TLR2 staining in cortex and medulla is lost and extended into the cytoplasm and the interstitium.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2682651&req=5

pone-0005704-g002: Expression and localization of TLR2 in UUO-injured kidney of TLR2+/+ mice at several time points.The amount of TLR2 mRNA (A) and protein (B) was markedly upregulated after UUO injury. Data are mean and SEM of six mice per group; *p<0.05. High magnification images (inserts) show that 3 and 7 days after UUO TLR2 was mainly located at the apical side of renal tubules in both cortex and medulla. After 14 days, apical tubular TLR2 staining in cortex and medulla is lost and extended into the cytoplasm and the interstitium.
Mentions: To evaluate the influence of fibrinogenesis at different stages on the expression and localization of TLR2 we next measured the amount of mRNA and protein in UUO-injured kidney of TLR2+/+ mice at several time points. This revealed that the amount of TLR2 mRNA was almost 5 times increased 3 days after UUO and continued to increase at later time points (Fig. 2A). The expression pattern of TLR2 protein followed a similar trend as compared to TLR2 mRNA expression. TLR2 protein was markedly upregulated 3, 7 and 14 after UUO-injury in kidneys of TLR2+/+ mice as compared with the contralateral unobstructed kidneys (Fig. 2B). High magnification images (inserts) show that 3 and 7 days after the induction of injury TLR2 was predominantly located at the apical side of renal tubules. After 14 days, apical TLR2 staining seems to be lost and in stead extended into the cytoplasm and interstitium. Control sections (t = 14), omitting primary antibody showed no overt staining (data not shown). Analysis of the expression of known endogenous stress ligands that potentially could activate TLR2, e.g. Gp96, biglycan, HMGB1, HSP60 and HSP70 [16], [19], [26]–[28] during progressive renal injury revealed a strong upregulation of the amount of biglycan (t = 7, 14), HMGB1 (t = 14), and Gp96 (t = 14) mRNA after UUO injury compared to contralateral kidneys (Fig. 3A). In line, we found a profound upregulation of tubulointerstitial Gp96, tubular biglycan and HMGB1 protein 14 days after the induction of UUO injury (Figure 3B). No upregulation was seen in HSP70 and HSP60 mRNA levels after UUO-injury (data not shown). Together, these data suggest that progressive renal injury leads to a marked enhancement of TLR2 and several main endogenous stress ligands.

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