Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice
Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice
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DOI：
10.1038/sj.ki.5000014
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发表时间：
2006-01-01
影响因子：
19.6
通讯作者：
Tesch, GH
中科院分区：
文献类型：
--
作者：
Chow, FY;Nikolic-Paterson, DJ;Tesch, GH
糖尿病肾病是由糖尿病环境引起的肾脏炎症反应。巨噬细胞在糖尿病肾脏中的聚集与单核细胞趋化蛋白-1(MCP-1)的局部上调有关；然而，巨噬细胞在肾脏损伤中的作用以及MCP-1在其增加中的重要性尚不清楚。因此，我们观察了链脲佐菌素(STZ)诱导的糖尿病肾病的进展，以探讨MCP-1介导的巨噬细胞聚集在糖尿病肾损害发生发展中的作用。在STZ治疗后2、8、12和18周，对血糖和血红蛋白A1c水平相当的MCP-1完整(+/+)和缺陷(-/-)小鼠进行肾脏病理检查。在MCP-1(+/+)小鼠中，糖尿病肾病的发展与肾脏MCP-1的产生增加有关，主要发生在肾小管上，这与我们在体外发现糖尿病环境中的元素(高糖和晚期糖基化终产物)直接刺激肾小管上皮细胞分泌MCP-1是一致的。18周的糖尿病导致MCP-1(+/+)小鼠的蛋白尿和血肌酐升高，但MCP-1(-/-)小鼠的这些肾脏损伤在很大程度上受到抑制。糖尿病MCP-1(-/-)小鼠对肾病的保护与显著减少肾小球和间质巨噬细胞聚集、组织学损害和肾脏纤维化有关。与糖尿病MCP-1(+/+)小鼠相比，糖尿病MCP-1(+/+)小鼠肾脏巨噬细胞表达活化标志物(诱导型一氧化氮合酶或唾液酸粘附素)的比例也较小。综上所述，我们的研究表明，单核细胞趋化蛋白-1介导的巨噬细胞聚集和激活在STZ诱导的小鼠糖尿病肾病的发生发展中起着关键作用。
Diabetic nephropathy involves a renal inflammatory response induced by the diabetic milieu. Macrophages accumulate in diabetic kidneys in association with the local upregulation of monocyte chemoattractant protein-1 ( MCP-1); however, the contribution of macrophages to renal injury and the importance of MCP-1 to their accrual are unclear. Therefore, we examined the progression of streptozotocin (STZ)-induced diabetic nephropathy in mice deficient in MCP-1 in order to explore the role of MCP-1-mediated macrophage accumulation in the development of diabetic kidney damage. Renal pathology was examined at 2, 8, 12 and 18 weeks after STZ treatment in MCP-1 intact (+/+) and deficient (-/-) mice with equivalent blood glucose and hemoglobin A1c levels. In MCP-1(+/+) mice, the development of diabetic nephropathy was associated with increased kidney MCP-1 production, which occurred mostly in tubules, consistent with our in vitro finding that elements of the diabetic milieu ( high glucose and advanced glycation end products) directly stimulate tubular MCP-1 secretion. Diabetes of 18 weeks resulted in albuminuria and elevated plasma creatinine in MCP-1(+/+) mice, but these aspects of renal injury were largely suppressed in MCP-1(-/-) mice. Protection from nephropathy in diabetic MCP-1(-/-) mice was associated with marked reductions in glomerular and interstitial macrophage accumulation, histological damage and renal fibrosis. Diabetic MCP- 1(+/+) mice also had a smaller proportion of kidney macrophages expressing markers of activation (inducible nitric oxide synthase or sialoadhesin) compared to diabetic MCP- 1( +/+) mice. In conclusion, our study demonstrates that MCP-1-mediated macrophage accumulation and activation plays a critical role in the development of STZ-induced mouse diabetic nephropathy.