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

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

doi:10.3389/fmed.2022.916620

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

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

Authors

Wei Wang¹, Song Wu¹, Amanda Y Wang^{2

3

4}, Tao Wu⁵, Haojun Luo¹, Jia Wei Zhao⁶, Jin Chen¹, Yi Li¹, Hanlu Ding¹

Affiliations

¹ 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.
² Renal and Metabolic Division, The George Institute for Global Health, University of New South Wales Australia, Newtown, NSW, Australia.
³ Department of Renal Medicine, Concord Repatriation General Hospital, Concord Clinical School, University of Sydney, Camperdown, NSW, Australia.
⁴ Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
⁵ Internal Medicine, Louisiana State University Health Science at Shreveport, Shreveport, LA, United States.
⁶ The Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia.

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. In vitro 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 via T0901317 or downregulating its expression via 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.

Keywords: diabetic nephropathy; factor XIII-A; inflammation; liver X receptor; thrombomodulin.

Grants and funding

This work was supported by the General Program of National Natural Science Foundation of China (81170680), the Basic Applied Projects of Science and Technology Department of Sichuan Province (2018JY0332), the Youth Foundation of Sichuan Academy of Medical Sciences, and Sichuan Provincial People's Hospital (3030503851). AW was supported by the National Heart Foundation Vanguard Grant, Australia (106075).