A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation
Hans-Joachim Anders, … , Peter J. Nelson, Detlef Schlöndorff
Hans-Joachim Anders, … , Peter J. Nelson, Detlef Schlöndorff
Published January 15, 2002
Citation Information: J Clin Invest. 2002;109(2):251-259. https://doi.org/10.1172/JCI14040.
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A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation

Abstract

The expression of chemokines and their receptors is thought to contribute to leukocyte infiltration and progressive renal fibrosis after unilateral ureter obstruction (UUO). We hypothesized that blocking the chemokine receptor CCR1 using the nonpeptide antagonist BX471 could reduce leukocyte infiltration and renal fibrosis after UUO. UUO kidneys from BX471-treated mice (day 0–10 and day 6–10) revealed a 40–60% reduction of interstitial macrophage and lymphocyte infiltrate compared with controls. Treated mice also showed a marked reduction of CCR1 and CCR5 mRNA levels, and FACS analysis showed a comparable reduction of CD8+/CCR5+ T cells. Markers of renal fibrosis, such as interstitial fibroblasts, interstitial volume, mRNA and protein expression for collagen I, were all significantly reduced by BX471-treatment compared with vehicle controls. By contrast treatment was ineffective when the drug was supplied only from days 0 to 5. In summary, blockade of CCR1 substantially reduces cell accumulation and renal fibrosis after UUO. Most interestingly, late onset of treatment is also effective. We therefore conclude that CCR1 blockade may represent a new therapeutic strategy for reducing cellular infiltration and renal fibrosis as major factors in the progression to end-stage renal failure.

Authors

Hans-Joachim Anders, Volker Vielhauer, Michael Frink, Yvonne Linde, Clemens D. Cohen, Simone M. Blattner, Matthias Kretzler, Frank Strutz, Matthias Mack, Hermann-Josef Gröne, James Onuffer, Richard Horuk, Peter J. Nelson, Detlef Schlöndorff

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Figure 5

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Leukocyte infiltration and renal fibrosis after UUO histology. Cortical ...
Leukocyte infiltration and renal fibrosis after UUO histology. Cortical renal sections were stained for CD45+ leukocytes. At 10 days after UUO (a) leukocytes accumulated in the peritubular interstitium in obstructed kidneys compared with unobstructed control kidneys (b). Treatment with BX471 from day 6 to 10 (c), as well as treatment for 10 days (d), reduced infiltration of CD45-positive leukocytes in UUO kidneys compared with a and b. No reduction was noted in UUO kidneys of mice treated with BX471 from days 0 to 5 (not shown). The accumulation of FSP1-positive fibroblasts in the peritubular interstitium 10 days after UUO (e) was reduced when BX471was given for 10 days (f) and from day 6 to 10 (latter not shown). Cortical renal sections were also silver stained to assess interstitial volume and fibrous tissue deposition. Note a marked widening of the interstitial space with deposition of fibrous tissue in areas of dilated tubules in obstructed kidneys at 10 days (g) compared with unobstructed control kidneys (h) of vehicle controls. Treatment with BX471 from days 6 to 10 reduced interstitial volume and matrix deposition (i), as well as BX471 treatment for 10 days (j), compared with g. No reduction was noted in UUO kidneys of mice treated with BX471 at days 0–5 (not shown). Tubular dilatation and tubular epithelial cell damage remained unchanged in all groups (original magnification ×400).