The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice

Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 wa...

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Main Authors: Ninichuk, Volha, Khandoga, Alexander G., Segerer, Stephan, Loetscher, Pius, Schlapbach, Achim, Revesz, Laszlo, Feifel, Roland, Khandoga, Andrej, Krombach, Fritz, Nelson, Peter J., Schlöndorff, Detlef, Anders, Hans-Joachim
פורמט: Artigo
שפה:English
יצא לאור: American Society for Investigative Pathology 2007
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Regular Articles
גישה מקוונת:https://ncbi.nlm.nih.gov/pmc/articles/PMC1829460/
https://ncbi.nlm.nih.gov/pubmed/17392166
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.2353/ajpath.2007.060937
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spelling pubmed-18294602007-10-01 The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice Ninichuk, Volha Khandoga, Alexander G. Segerer, Stephan Loetscher, Pius Schlapbach, Achim Revesz, Laszlo Feifel, Roland Khandoga, Andrej Krombach, Fritz Nelson, Peter J. Schlöndorff, Detlef Anders, Hans-Joachim Am J Pathol Regular Articles Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-β1, and collagen I-α1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy. American Society for Investigative Pathology 2007-04 /pmc/articles/PMC1829460/ /pubmed/17392166 http://dx.doi.org/10.2353/ajpath.2007.060937 Text en Copyright © American Society for Investigative Pathology
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Regular Articles
spellingShingle Regular Articles
Ninichuk, Volha
Khandoga, Alexander G.
Segerer, Stephan
Loetscher, Pius
Schlapbach, Achim
Revesz, Laszlo
Feifel, Roland
Khandoga, Andrej
Krombach, Fritz
Nelson, Peter J.
Schlöndorff, Detlef
Anders, Hans-Joachim
The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
description Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-β1, and collagen I-α1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.
author Ninichuk, Volha
Khandoga, Alexander G.
Segerer, Stephan
Loetscher, Pius
Schlapbach, Achim
Revesz, Laszlo
Feifel, Roland
Khandoga, Andrej
Krombach, Fritz
Nelson, Peter J.
Schlöndorff, Detlef
Anders, Hans-Joachim
author_facet Ninichuk, Volha
Khandoga, Alexander G.
Segerer, Stephan
Loetscher, Pius
Schlapbach, Achim
Revesz, Laszlo
Feifel, Roland
Khandoga, Andrej
Krombach, Fritz
Nelson, Peter J.
Schlöndorff, Detlef
Anders, Hans-Joachim
author_sort Ninichuk, Volha
title The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
title_short The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
title_full The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
title_fullStr The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
title_full_unstemmed The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
title_sort role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice
publisher American Society for Investigative Pathology
publisher_facet American Society for Investigative Pathology
publishDate 2007
url https://ncbi.nlm.nih.gov/pmc/articles/PMC1829460/
https://ncbi.nlm.nih.gov/pubmed/17392166
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.2353/ajpath.2007.060937
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