Acute Kidney Injury-Induced Circulating TNFR1/2 Elevations Correlate with Persistent Kidney Injury and Progression to Fibrosis.
Acute Kidney Injury-Induced Circulating TNFR1/2 Elevations Correlate with Persistent Kidney Injury and Progression to Fibrosis.
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急性肾脏损伤引起的循环TNFR1/2高程与持续的肾脏损伤和纤维化进展相关。
作者：
循环肿瘤坏死因子受体1和2 （cTNFR1/2）水平升高预测慢性肾脏疾病（CKD）进展；然而，它们的释放机制仍然未知。急性肾损伤（AKI）是否驱动cTNFR1/2升高以及它们是否预测AKI后的疾病结局仍然未知。在这项研究中，我们使用AKI患者的血清和尿液样本、肾损伤小鼠模型（缺血性、阻塞性和毒性）、纤维化进展、肾切除术和相关的单细胞rna测序数据集来实验测试肾损伤对cTNFR1/2水平的作用。我们发现，在所有肾损伤小鼠模型中，TNFR1/2血清和尿液水平在损伤后一小时内开始高度升高，并与损伤的严重程度相关。与此一致的是，AKI患者血清和尿液TNFR1/2水平升高，且与肾衰竭的严重程度相关。AKI后肾组织中TNFR1/2的表达仅轻微升高，双侧肾切除术导致cTNFR1/2强烈升高，提示这些受体通过肾外源释放。健康小鼠注射尿毒症毒素硫酸吲哚酚可诱导cTNFR1/2中度升高。此外，TNF中和不影响AKI后早期cTNFR1/2升高。这些数据表明，AKI中的cTNFR1/2水平并不反映损伤诱导的TNF活性，而是对肾功能丧失和尿毒症的快速反应。与传统的疾病生物标志物（如血清肌酐或BUN）相比，cTNFR1/2水平在严重肾损伤后数周内仍保持升高。在这些较晚的时间点，cTNFR1/2水平与剩余肾损伤呈正相关。在aki向ckd过渡期间，TNFR1/2肾脏表达和cTNFR2水平的升高与肾纤维化水平相关。总之，我们的数据表明，肾损伤导致cTNFR1/2血清水平急性升高，这与肾功能呈负相关。在aki向ckd过渡期间，肾损伤后持续的TNFR1/2升高反映了持续的组织损伤和肾纤维化的进展。
Elevated levels of circulating tumor necrosis factor receptors 1 and 2 (cTNFR1/2) predict chronic kidney disease (CKD) progression; however, the mechanisms of their release remain unknown. Whether acute kidney injury (AKI) drives cTNFR1/2 elevations and whether they predict disease outcomes after AKI remain unknown. In this study, we used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, and toxic), and progression to fibrosis, nephrectomy, and related single-cell RNA-sequencing datasets to experimentally test the role of kidney injury on cTNFR1/2 levels. We show that TNFR1/2 serum and urine levels are highly elevated in all of the mouse models of kidney injury tested, beginning within one hour post injury, and correlate with its severity. Consistent with this, serum and urine TNFR1/2 levels are increased in AKI patients and correlate with the severity of kidney failure. Kidney tissue expression of TNFR1/2 after AKI is only slightly increased and bilateral nephrectomies lead to strong cTNFR1/2 elevations, suggesting the release of these receptors by extrarenal sources. The injection of the uremic toxin indoxyl sulfate in healthy mice induces moderate cTNFR1/2 elevations. Moreover, TNF neutralization does not affect early cTNFR1/2 elevations after AKI. These data suggest that cTNFR1/2 levels in AKI do not reflect injury-induced TNF activity, but rather a rapid response to loss of kidney function and uremia. In contrast to traditional disease biomarkers, such as serum creatinine or BUN, cTNFR1/2 levels remain elevated for weeks after severe kidney injury. At these later timepoints, cTNFR1/2 levels positively correlate with remaining kidney injury. During the AKI-to-CKD transition, elevations of TNFR1/2 kidney expression and of cTNFR2 levels correlate with kidney fibrosis levels. In conclusion, our data demonstrate that kidney injury drives acute increases in cTNFR1/2 serum levels, which negatively correlate with kidney function. Sustained TNFR1/2 elevations after kidney injury during AKI-to-CKD transition reflect persistent tissue injury and progression to kidney fibrosis.
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