Reduced Glomerular Endothelial Thrombomodulin Is Associated with Glomerular Macrophage Infiltration in Diabetic Nephropathy

Cleo C.L Van Aanhold,Kyra L Dijkstra,Manon Bos,Ron Wolterbeek,Bernard M Van Den Berg,Jan A Bruijn,Ingeborg M Bajema,Hans J Baelde

doi:10.1016/j.ajpath.2021.02.002

Cleo C.L Van Aanhold, Kyra L Dijkstra + Show 6 more

Open Access

https://doi.org/10.1016/j.ajpath.2021.02.002

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Abstract

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin.

Highlights

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis
This study shows that in diabetes, glomerular thrombomodulin is decreased at the protein level but increased at the mRNA level, and the reduction in glomerular thrombomodulin protein is associated with an increased infiltration of macrophages in the glomeruli
Blocking the endothelin A receptor restores glomerular thrombomodulin protein levels in a diabetic mouse model. These findings suggest that the reduction in glomerular endothelial thrombomodulin occurs at an early stage of diabetic microvascular damage and contributes to glomerular inflammation in diabetic nephropathy (DN)

Summary

Introduction

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. Glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the Western world,[1] occurring in approximately 40% of patients with diabetes mellitus.[2] Impaired function of the glomerular endothelial cells occurs in the early stages of diabetic kidney damage, with a reduction in the glomerular endothelial glycocalyx and altered expression of endothelial adhesion proteins contributing to inflammation and fibrosis.[3,4] The thrombomodulin/protein C signaling pathway is critical for maintaining glomerular endothelial homeostasis and preventing inflammation.[5] animal studies indicate that impaired glomerular thrombomodulin signaling contributes to the pathogenesis of DN.[6].

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