Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong.
J Am Soc Nephrol. 2012 Jan;23(1):86-102. doi: 10.1681/ASN.2010111210. Epub 2011 Oct 21.
Inflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease from other causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time- and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IκB/NF-κB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IκB/NF-κB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucose-treated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-κB activation, tubular CCL-2 expression, and interstitial macrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathway may promote tubulointerstitial inflammation in diabetic nephropathy.
炎症导致糖尿病肾病的肾小管间质病变。Toll 样受体（TLR）调节免疫反应和炎症性疾病，但它们在糖尿病肾病中的作用尚不清楚。在这项研究中，我们发现与正常肾脏和其他原因引起的肾脏疾病相比，糖尿病肾病患者的肾脏肾小管中 TLR4 的表达增加，而 TLR2 的表达没有增加。肾小管 TLR4 表达的强度与间质巨噬细胞浸润和血红蛋白 A1c 水平直接相关，与估计肾小球滤过率成反比。肾小管还在糖尿病肾病中上调了内源性 TLR4 配体高迁移率族蛋白 B1。在体外，高葡萄糖通过蛋白激酶 C 激活以时间和剂量依赖的方式诱导 TLR4 表达，导致 IκB/NF-κB 激活，从而上调人近端肾小管上皮细胞中 IL-6 和趋化因子（C-C 基序）配体 2（CCL-2）的表达。用小干扰 RNA 沉默 TLR4 可减弱高葡萄糖诱导的 IκB/NF-κB 激活，抑制下游 IL-6 和 CCL-2 的合成，并损害高葡萄糖处理的近端肾小管细胞条件培养基诱导单核细胞迁移的能力。我们使用 TLR4 中和抗体观察到类似的效果。最后，链脲佐菌素诱导的糖尿病和单侧肾切除 TLR4 缺陷小鼠的白蛋白尿、肾功能障碍、肾皮质 NF-κB 激活、肾小管 CCL-2 表达和间质巨噬细胞浸润均明显低于野生型动物。总之，这些数据表明 TLR4 介导的途径可能促进糖尿病肾病的肾小管间质炎症。
