Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
J Am Soc Nephrol. 2010 Aug;21(8):1299-308. doi: 10.1681/ASN.2009070722. Epub 2010 Jul 1.
Toll-like receptors (TLRs) can orchestrate an inflammatory response upon activation by pathogen-associated motifs and release of endogenous stress ligands during tissue injury. The kidney constitutively expresses most TLRs, including TLR4. The function of TLR4 during the inflammation, tubular atrophy, and fibrosis that accompany progressive renal injury is unknown. Here, we subjected wild-type (WT) and TLR4-deficient mice to unilateral ureteral obstruction and observed elevated levels of TLR4 mRNA in the kidney after obstruction. One day after unilateral ureteral obstruction, TLR4-deficient mice had fewer proliferating tubular epithelial cells and more tubular damage than WT mice; however, TLR4-deficient mice developed considerably less renal fibrosis despite decreased matrix metalloproteinase activity and without significant differences in myofibroblast accumulation. In vitro, TLR4-deficient primary tubular epithelial cells and myofibroblasts produced significantly less type I collagen mRNA after TGF-beta stimulation than WT cells. The reduced fibrosis in TLR4-deficient mice associated with an upregulation of Bambi, a negative regulator of TGF-beta signaling. In conclusion, TLR4 attenuates tubular damage but promotes renal fibrosis by modulating the susceptibility of renal cells to TGF-beta. These data suggest that TLR4 signaling may be a therapeutic target for the prevention of renal fibrosis.
Toll 样受体 (TLRs) 在识别病原体相关分子模式并在组织损伤时释放内源性应激配体后，能够协调炎症反应。肾脏中大多数 TLRs（包括 TLR4）持续表达。TLR4 在渐进性肾损伤伴随的炎症、肾小管萎缩和纤维化中的功能尚不清楚。在这里，我们使野生型 (WT) 和 TLR4 缺陷型小鼠接受单侧输尿管梗阻，并观察到梗阻后肾脏中 TLR4 mRNA 水平升高。单侧输尿管梗阻后 1 天，TLR4 缺陷型小鼠的增殖性肾小管上皮细胞比 WT 小鼠少，肾小管损伤更多；然而，TLR4 缺陷型小鼠的肾纤维化明显较少，尽管基质金属蛋白酶活性降低，但肌成纤维细胞积聚没有显著差异。在体外，TLR4 缺陷型原代肾小管上皮细胞和肌成纤维细胞在 TGF-β刺激后产生的 I 型胶原 mRNA 明显少于 WT 细胞。TLR4 缺陷型小鼠的纤维化减少与 TGF-β 信号的负调控因子 Bambi 的上调有关。总之，TLR4 通过调节肾脏细胞对 TGF-β的敏感性来减轻肾小管损伤，但促进肾纤维化。这些数据表明，TLR4 信号可能是预防肾纤维化的治疗靶点。
