The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy
The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy
复制标题
TLR4 拮抗剂 CRX-526 可预防晚期糖尿病肾病。
DOI：
10.1038/ki.2013.11
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发表时间：
2013-05-01
影响因子：
19.6
通讯作者：
Tang, Sydney C. W.
中科院分区：
文献类型：
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作者：
Lin, Miao;Yiu, Wai Han;Tang, Sydney C. W.
我们最近发现，Toll样受体（TLR）TLR 4在人类糖尿病肾脏中过表达，这可能会促进肾小管炎症。在这里，我们探讨了TLR 4拮抗剂CRX-526是否具有减轻野生型和内皮型一氧化氮合酶（eNOS）敲除小鼠肾损伤和减缓晚期糖尿病肾病进展的治疗潜力。在后者中，内源性TLR 4配体，高迁移率族蛋白1，上调超过野生型动物。链脲佐菌素诱导糖尿病后四周，给小鼠注射CRX-526或载体8周。CRX-526显著降低糖尿病小鼠的白蛋白尿和血尿素氮，而不改变血糖和收缩压。CRX-526可减轻肾小球肥大、肾小球硬化和肾小管间质损伤，这与趋化因子（C-C基序）配体（CCL）-2、骨桥蛋白、CCL-5过表达、随后的巨噬细胞浸润和胶原沉积减少有关。CRX-526抑制高糖诱导的人近端肾小管上皮细胞骨桥蛋白表达上调和NF-κB核转位。因此，我们提供的证据表明，抑制TLR 4与合成拮抗剂CRX-526赋予eNOS敲除糖尿病小鼠晚期糖尿病肾病肾保护作用。
We recently showed that Toll-like receptor (TLR) TLR4 was overexpressed in the human diabetic kidney, which could promote tubular inflammation. Here we explored whether the TLR4 antagonist, CRX-526, has therapeutic potential to attenuate renal injuries and slow the progression of advanced diabetic nephropathy in wild-type and endothelial nitric oxide synthase (eNOS) knockout mice. In the latter, the endogenous TLR4 ligand, high-mobility group box 1, was upregulated more than in wild-type animals. Four weeks after streptozotocin induction of diabetes, mice were injected with either CRX-526 or vehicle for 8 weeks. CRX-526 significantly reduced albuminuria and blood urea nitrogen without altering blood glucose and systolic blood pressure in diabetic mice. Glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial injury were attenuated by CRX-526, which was associated with decreased chemokine (C-C motif) ligand (CCL)-2, osteopontin, CCL-5 overexpression, subsequent macrophage infiltration, and collagen deposition. These effects were associated with inhibition of TGF-β overexpression and NF-κB activation.In vitro, CRX-526 inhibited high glucose-induced osteopontin upregulation and NF-κB nuclear translocation in cultured human proximal tubular epithelial cells. Thus, we provided evidence that inhibition of TLR4 with the synthetic antagonist CRX-526 conferred renoprotective effects in eNOS knockout diabetic mice with advanced diabetic nephropathy.