The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB
The Inflammatory Cytokines TWEAK and TNFα Reduce Renal Klotho Expression through NFκB
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DOI：
10.1681/asn.2010101073
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发表时间：
2011-07-01
影响因子：
13.6
通讯作者：
Sanz, Ana B.
中科院分区：
文献类型：
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作者：
Moreno, Juan A.;Izquierdo, Maria C.;Sanz, Ana B.
促炎性细胞因子有助于肾损伤，但肾细胞内的下游效应器还不清楚。一个候选效应子是Klotho，一种由肾细胞表达的具有抗衰老特性的蛋白质; Klotho缺陷小鼠具有加速衰老样表型，包括血管损伤和肾损伤。是否促炎细胞因子，如TNF和TNF样弱诱导凋亡（TWEAK），调节Klotho是未知的。在小鼠中，TWEAK的外源性施用降低了Klotho在肾脏中的表达。在叶酸诱导的急性肾损伤的情况下，阻断或不存在TWEAK消除了肾和血浆Klotho水平的损伤相关降低。在MCT肾小管细胞系中，TWEAK、TNF α和siRNA介导的I κ B α敲低均激活NF κ B并降低Klotho表达。此外，用孤雌菊抑制NF κ B可防止TWEAK或TNF α诱导的Klotho下调。抑制组蛋白去乙酰化酶逆转TWEAK诱导的Klotho下调，染色质免疫沉淀显示，TWEAK促进RelA结合Klotho启动子，诱导其去乙酰化。总之，炎性细胞因子如TWEAK和TNF α通过NF κ B依赖性机制下调Klotho表达。这些结果可以部分解释炎症与器官加速老化的疾病之间的关系，包括CKD。
Proinflammatory cytokines contribute to renal injury, but the downstream effectors within kidney cells are not well understood. One candidate effector is Klotho, a protein expressed by renal cells that has antiaging properties; Klotho-deficient mice have an accelerated aging-like phenotype, including vascular injury and renal injury. Whether proinflammatory cytokines, such as TNF and TNF-like weak inducer of apoptosis (TWEAK), modulate Klotho is unknown. In mice, exogenous administration of TWEAK decreased expression of Klotho in the kidney. In the setting of acute kidney injury induced by folic acid, the blockade or absence of TWEAK abrogated the injury-related decrease in renal and plasma Klotho levels. TWEAK, TNF alpha, and siRNA-mediated knockdown of I kappa B alpha all activated NF kappa B and reduced Klotho expression in the MCT tubular cell line. Furthermore, inhibition of NF kappa B with parthenolide prevented TWEAK- or TNF alpha-induced downregulation of Klotho. Inhibition of histone deacetylase reversed TWEAK-induced downregulation of Klotho, and chromatin immunoprecipitation showed that TWEAK promotes RelA binding to the Klotho promoter, inducing its deacetylation. In conclusion, inflammatory cytokines, such as TWEAK and TNF alpha, downregulate Klotho expression through an NF kappa B-dependent mechanism. These results may partially explain the relationship between inflammation and diseases characterized by accelerated aging of organs, including CKD.