TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury
TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury
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DOI：
10.1042/cs20170262
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发表时间：
2018-08-31
期刊：
影响因子：
6
通讯作者：
de Almeida, Danilo Candido
中科院分区：
文献类型：
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作者：
Andrade-Silva, Magaiver;Cenedeze, Marcos Antonio;de Almeida, Danilo Candido
急性肾损伤(AKI)是一种炎症性疾病，Toll样受体(TLRs)信号通路在其中发挥重要作用。TLRs的激活导致几种炎性细胞因子的产生，从而导致进一步的肾脏损害。相反，TLRs是自噬诱导的关键参与者，自噬诱导与对顺铂诱导的AKI的保护功能有关。因此，本研究旨在评价TLR2和TLR4分子在顺铂诱导AKI过程中的特异性参与。作为补充，我们还研究了TLRs和血红素加氧酶-1(HO-1)之间的联系，HO-1是一种承诺的细胞保护分子。首先，我们观察到，即使在免疫特权的微环境下，只有TLR2的缺失而不是TLR4的缺失会加剧小鼠的肾功能障碍、组织损伤和死亡率。其次，我们证明与TLR4KO相比，TLR2基因敲除(KO)小鼠的自噬相关标记物的表达较低。使用来自两只KO小鼠的肾小管上皮细胞，在体外也证实了类似的参数。为了测试HO-1和TLRs之间的相互作用，在顺铂治疗的TLR2和TLR4 KO小鼠中给予HO-1内部诱导剂氯化血红素，并检测到其对整体肾组织参数的改善。然而，这种保护在TLR2 KO小鼠中不那么明显。综上所述，我们证明TLR2在顺铂诱导的AKI进展中起到保护作用，部分是通过与自噬上调相关的机制，考虑到它与HO-1的相互作用可以促进肾组织的恢复。
Acute kidney injury (AKI) is considered an inflammatory disease in which toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy-associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover.