Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
J Hypertens. 2009 Oct;27(10):2063-73. doi: 10.1097/HJH.0b013e3283300192.
Renal artery stenosis (RAS) causes renovascular hypertension and renal damage, which may result from tissue inflammation. We have previously shown that the kidney in RAS exhibits increased expression of monocyte chemoattractant protein (MCP)-1, but its contribution to renal injury remained unknown. This study tested the hypothesis that MCP-1 contributes to renal injury and dysfunction in the stenotic kidney.
Kidney hemodynamics, function, and endothelial function were quantified in pigs after 10 weeks of experimental RAS (n = 7), RAS supplemented with the MCP-1 inhibitor bindarit (RAS + bindarit, 50 mg/kg/day orally, n = 6), and normal controls (n = 8). Renal inflammation was assessed by the immunoreactivity of MCP-1, its receptor chemotactic cytokine receptor 2, and NFkappaB, and oxidative stress by nicotinamide adenine dinucleotide phosphate-oxidase expression and in-situ superoxide production. Renal microvascular density was evaluated by micro-CT and fibrosis by trichrome staining, collagen-I immunostaining, and hydroxyproline content.
After 10 weeks of RAS, blood pressure was similarly elevated in RAS and RAS + bindarit. Compared with normal controls, stenotic RAS kidneys had decreased renal blood flow (5.4 +/- 1.6 vs. 11.4 +/- 1.0 ml/min/kg, P < 0.05) and glomerular filtration rate and impaired endothelial function, which were significantly improved in bindarit-treated RAS pigs (to 8.4 +/- 0.8 ml/min/kg, P < 0.05 vs. RAS). Furthermore, bindarit markedly decreased tubulointerstitial (but not vascular) oxidative stress, inflammation, and fibrosis, and slightly increased renal microvascular density. The impaired renovascular endothelial function, increased oxidative-stress, and fibrosis in the contralateral kidney were also improved by bindarit.
MCP-1 contributes to functional and structural impairment in the kidney in RAS, mainly in the tubulointerstitial compartment. Its inhibition confers renoprotective effects by blunting renal inflammation and thereby preserving the kidney in chronic RAS.
肾动脉狭窄（RAS）引起肾血管性高血压和肾脏损害，这可能是由于组织炎症引起的。我们之前已经表明，RAS 中的肾脏表现出单核细胞趋化蛋白-1（MCP-1）的表达增加，但它对肾脏损伤的贡献仍不清楚。本研究检验了以下假设，即 MCP-1 有助于狭窄肾脏中的肾脏损伤和功能障碍。
在实验性 RAS（n = 7）、RAS 加 MCP-1 抑制剂 bindarit（RAS + bindarit，每天 50mg/kg 口服，n = 6）和正常对照组（n = 8）10 周后，量化了猪的肾脏血液动力学、功能和内皮功能。通过 MCP-1、其受体趋化因子受体 2 和 NFkappaB 的免疫反应性评估肾脏炎症，通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶表达和原位超氧化物产生评估氧化应激。通过 micro-CT 评估肾脏微血管密度，通过三染色法、胶原蛋白-I 免疫染色和羟脯氨酸含量评估纤维化。
在 RAS 后 10 周，RAS 和 RAS + bindarit 的血压升高相似。与正常对照组相比，狭窄 RAS 肾脏的肾血流量减少（5.4 +/- 1.6 对 11.4 +/- 1.0 ml/min/kg，P < 0.05）和肾小球滤过率受损，内皮功能受损，在 RAS 猪中，bindarit 治疗显著改善（至 8.4 +/- 0.8 ml/min/kg，P < 0.05 对 RAS）。此外，bindarit 显著降低了肾小管间质（但不是血管）的氧化应激、炎症和纤维化，并轻微增加了肾脏微血管密度。对侧肾脏的血管内皮功能障碍、氧化应激增加和纤维化也通过 bindarit 得到改善。
MCP-1 有助于 RAS 中肾脏的功能和结构损伤，主要在肾小管间质区。其抑制通过减弱肾脏炎症来提供肾脏保护作用，从而在慢性 RAS 中保护肾脏。
