The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice
The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice
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DOI：
10.2353/ajpath.2007.060937
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发表时间：
2007-04-01
影响因子：
6
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Ninichuk, Volha;Khandoga, Alexander G.;Anders, Hans-Joachim
糖尿病肾病与间质巨噬细胞浸润有关，但它们在疾病进展中的作用尚不清楚。我们通过阻断趋化因子受体(CCR)1来解决这个问题，因为CCR1介导巨噬细胞向肾间质的募集。事实上，当CCR1被一种新的口服CCR1拮抗剂131,5923阻断时，单肾切除的晚期糖尿病肾病雄性db/db小鼠的体外标记巨噬细胞的募集显著减少，5~6个月口服BL5923(60 mg/kg，每天两次)可减少间质巨噬细胞的数量；这与单肾切除db/db小鼠Ki-67增殖的肾小管上皮细胞和间质细胞数量减少、肾小管萎缩和间质纤维化有关。CCR1拮抗剂对肾小球病理和蛋白尿无影响。BL5923可降低CCL2、CCR1、CCR2、CCR5、转化生长因子-β1和I型胶原基因的表达。因此，我们确定了间质巨噬细胞在2型糖尿病db/db小鼠肾小管间质损伤、肾小管周围微血管丧失、间质炎症和纤维化中所起的先前未知的作用。这些数据表明，口服CCR1拮抗剂BL5923是治疗晚期糖尿病肾病的一种潜在疗法。
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 131,5923, 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; m 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-beta 1, and collagen I-alpha 1 when compared with untreated uninephrectomized male db/db mice of die 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.