由LXR激动剂驱动的血栓调节蛋白激活可减轻糖尿病肾病中的肾损伤。

Thrombomodulin activation driven by LXR agonist attenuates renal injury in diabetic nephropathy.

作者信息

Wang Wei, Wu Song, Wang Amanda Y, Wu Tao, Luo Haojun, Zhao Jia Wei, Chen Jin, Li Yi, Ding Hanlu

机构信息

Renal Division and Institute of Nephrology, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

Renal and Metabolic Division, The George Institute for Global Health, University of New South Wales Australia, Newtown, NSW, Australia.

出版信息

Front Med (Lausanne). 2023 Jan 9;9:916620. doi: 10.3389/fmed.2022.916620. eCollection 2022.

DOI:10.3389/fmed.2022.916620

PMID:36698821

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9870310/

Abstract

OBJECTIVE

Inflammation and thrombosis are recognized as interrelated biological processes. Both thrombomodulin (TM) and factor XIII-A (FXIII-A) are involved in inflammation and coagulation process. However, their role in the pathogenesis of diabetic nephropathy (DN) remains unclear. study, the liver X receptor (LXR) agonist T0901317 can up-regulate the expression of TM in glomerular endothelial cells. Now we evaluated the interaction between TM activation and FXIII-A and their effects against renal injury.

METHODS

We first evaluated the serum levels of FXIII-A and TM and the expression of TM, LXR-α and FXIII-A in renal tissues of patients with biopsy-proven DN. We then analyzed the expression of TM, LXR-α and FXIII-A in renal tissues of db/db DN mice after upregulating TM expression T0901317 or downregulating its expression transfection of TM shRNA-loaded adenovirus. We also investigated the serum levels of Tumor necrosis factor (TNF)-α, Interleukin (IL)-6, creatinine, and urinary microalbumin level in db/db mice.

RESULTS

Our study showed that elevations in serum levels of FXIII-A positively correlated to the serum levels of TM and were also associated with end-stage kidney disease in patients with DN. The number of TM cells in the renal tissues of patients with DN negatively correlated with the number of FXIII-A cells and positively correlated with the number of LXR-α cells and estimated glomerular filtration rate (eGFR), whereas the number of FXIII-A cells negatively correlated with the eGFR.

CONCLUSION

Thrombomodulin activation with T0901317 downregulated FXIII-A expression in the kidney tissue and alleviated renal injury in db/db mice.

摘要

目的

炎症和血栓形成被认为是相互关联的生物学过程。血栓调节蛋白（TM）和凝血因子 XIII-A（FXIII-A）均参与炎症和凝血过程。然而，它们在糖尿病肾病（DN）发病机制中的作用仍不清楚。研究表明，肝脏 X 受体（LXR）激动剂 T0901317 可上调肾小球内皮细胞中 TM 的表达。现在我们评估了 TM 激活与 FXIII-A 之间的相互作用及其对肾损伤的影响。

方法

我们首先评估了经活检证实的 DN 患者血清中 FXIII-A 和 TM 的水平以及肾组织中 TM、LXR-α 和 FXIII-A 的表达。然后，我们通过 T0901317 上调 TM 表达或通过转染负载 TM shRNA 的腺病毒下调其表达，分析了 db/db DN 小鼠肾组织中 TM、LXR-α 和 FXIII-A 的表达。我们还研究了 db/db 小鼠血清中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、肌酐水平以及尿微量白蛋白水平。

结果

我们的研究表明，血清中 FXIII-A 水平的升高与 TM 血清水平呈正相关，并且也与 DN 患者的终末期肾病有关。DN 患者肾组织中 TM 细胞数量与 FXIII-A 细胞数量呈负相关，与 LXR-α 细胞数量和估计肾小球滤过率（eGFR）呈正相关，而 FXIII-A 细胞数量与 eGFR 呈负相关。