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

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

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.916620

DOI=10.3389/fmed.2022.916620

ISSN=2296-858X

ABSTRACT=<sec><title>Objective</title><p>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. <italic>In vitro</italic> 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.</p></sec><sec><title>Methods</title><p>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 <italic>via</italic> T0901317 or downregulating its expression <italic>via</italic> 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.</p></sec><sec><title>Results</title><p>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<sup>+</sup> cells in the renal tissues of patients with DN negatively correlated with the number of FXIII-A<sup>+</sup> cells and positively correlated with the number of LXR-α<sup>+</sup> cells and estimated glomerular filtration rate (eGFR), whereas the number of FXIII-A<sup>+</sup> cells negatively correlated with the eGFR.</p></sec><sec><title>Conclusion</title><p>Thrombomodulin activation with T0901317 downregulated FXIII-A expression in the kidney tissue and alleviated renal injury in db/db mice.</p></sec>