Limits...
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.

Show MeSH

Related in: MedlinePlus

Apoptotic and proliferating tubular cells in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of apoptotic (t = 7) tubular cells and proliferating (t = 14) cells were significantly lower in kidneys from TLR2−/− mice compared to kidneys from TLR2+/+ animals as counted in 10 randomly selected high-power fields. Cells were counted on renal tissue sections stained for active caspase-3 (apoptosis) and Ki67 (proliferation). Due to severe tubular atrophy, it is impossible to identify apoptotic TECs after 14 days. Therefore we analyzed at this time point the total amount of apoptotic cells (both interstitial cells and tubular cells). Data are mean and SEM of six mice per group, *p<0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2682651&req=5

pone-0005704-g008: Apoptotic and proliferating tubular cells in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of apoptotic (t = 7) tubular cells and proliferating (t = 14) cells were significantly lower in kidneys from TLR2−/− mice compared to kidneys from TLR2+/+ animals as counted in 10 randomly selected high-power fields. Cells were counted on renal tissue sections stained for active caspase-3 (apoptosis) and Ki67 (proliferation). Due to severe tubular atrophy, it is impossible to identify apoptotic TECs after 14 days. Therefore we analyzed at this time point the total amount of apoptotic cells (both interstitial cells and tubular cells). Data are mean and SEM of six mice per group, *p<0.05.

Mentions: Tubulointerstitial injury in UUO-injury can result in an imbalance between tubular epithelial cell (TEC) apoptosis and proliferation. We found that apoptosis occurred predominantly in the renal cortex and increased significantly after 3 days of obstruction. A marked decrease in the number of apoptotic TECs was present in obstructed kidneys of TLR2−/− mice compared to TLR2+/+ kidneys at day 7 (Fig. 8A). As it is difficult, if not impossible, to identify apoptotic TECs after 14 days when tubular atrophy was very severe we analyzed at this time point the total amount of apoptotic cells and found a similar trend as seen after 7 days. Tubular proliferation of cortical tubules became prominent on day 3 post-UUO (Fig. 8B). However, no differences were found between TLR2−/− and TLR2+/+ at 3 and 7 days after obstruction. Fourteen days after obstruction, TLR2−/− mice showed significantly less proliferation of cells than TLR2+/+ animals.


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)

Apoptotic and proliferating tubular cells in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of apoptotic (t = 7) tubular cells and proliferating (t = 14) cells were significantly lower in kidneys from TLR2−/− mice compared to kidneys from TLR2+/+ animals as counted in 10 randomly selected high-power fields. Cells were counted on renal tissue sections stained for active caspase-3 (apoptosis) and Ki67 (proliferation). Due to severe tubular atrophy, it is impossible to identify apoptotic TECs after 14 days. Therefore we analyzed at this time point the total amount of apoptotic cells (both interstitial cells and tubular cells). 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-g008: Apoptotic and proliferating tubular cells in kidneys from TLR2+/+ (□) and TLR2−/− (▪) mice 3, 7, and 14 days after UUO or in contralateral kidneys.The number of apoptotic (t = 7) tubular cells and proliferating (t = 14) cells were significantly lower in kidneys from TLR2−/− mice compared to kidneys from TLR2+/+ animals as counted in 10 randomly selected high-power fields. Cells were counted on renal tissue sections stained for active caspase-3 (apoptosis) and Ki67 (proliferation). Due to severe tubular atrophy, it is impossible to identify apoptotic TECs after 14 days. Therefore we analyzed at this time point the total amount of apoptotic cells (both interstitial cells and tubular cells). Data are mean and SEM of six mice per group, *p<0.05.
Mentions: Tubulointerstitial injury in UUO-injury can result in an imbalance between tubular epithelial cell (TEC) apoptosis and proliferation. We found that apoptosis occurred predominantly in the renal cortex and increased significantly after 3 days of obstruction. A marked decrease in the number of apoptotic TECs was present in obstructed kidneys of TLR2−/− mice compared to TLR2+/+ kidneys at day 7 (Fig. 8A). As it is difficult, if not impossible, to identify apoptotic TECs after 14 days when tubular atrophy was very severe we analyzed at this time point the total amount of apoptotic cells and found a similar trend as seen after 7 days. Tubular proliferation of cortical tubules became prominent on day 3 post-UUO (Fig. 8B). However, no differences were found between TLR2−/− and TLR2+/+ at 3 and 7 days after obstruction. Fourteen days after obstruction, TLR2−/− mice showed significantly less proliferation of cells than TLR2+/+ animals.

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