title: Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice.
abstract: Chronic kidney disease pathogenesis involves both tubular and vascular injuries. Despite abundant investigations to identify the risk factors, the involvement of chronic endothelial dysfunction in developing nephropathies is insufficiently explored. Previously, soluble thrombomodulin (sTM), a cofactor in the activation of protein C, has been shown to protect endothelial function in models of acute kidney injury. In this study, the role for sTM in treating chronic kidney disease was explored by employing a mouse model of chronic vascular activation using endothelial-specific TNF-α-expressing (tie2-TNF) mice. Analysis of kidneys from these mice after 3 mo showed no apparent phenotype, whereas 6-mo-old mice demonstrated infiltration of CD45-positive leukocytes accompanied by upregulated gene expression of inflammatory chemokines, markers of kidney injury, and albuminuria. Intervention with murine sTM with biweekly subcutaneous injections during this window of disease development between months 3 and 6 prevented the development of kidney pathology. To better understand the mechanisms of these findings, we determined whether sTM could also prevent chronic endothelial cell activation in vitro. Indeed, treatment with sTM normalized increased chemokines, adhesion molecule expression, and reduced transmigration of monocytes in continuously activated TNF-expressing endothelial cells. Our results suggest that vascular inflammation associated with vulnerable endothelium can contribute to loss in renal function as suggested by the tie2-TNF mice, a unique model for studying the role of vascular activation and inflammation in chronic kidney disease. Furthermore, the ability to restore the endothelial balance by exogenous administration of sTM via downregulation of specific adhesion molecules and chemokines suggests a potential for therapeutic intervention in kidney disease associated with chronic inflammation.
authors: Indiana Center for Vascular Biology and Medicine, IU School of Medicine, 975 W. Walnut St., Med. Lib./Rm. IB442B, Indianapolis, IN 46202, USA. rgangara@iupui.edu
authors: Gangaraju
authors: G
authors: Rajashekhar
authors: Akanksha
authors: A
authors: Gupta
authors: Abby
authors: A
authors: Marin
authors: Jessica
authors: J
authors: Friedrich
authors: Antje
authors: A
authors: Willuweit
authors: David T
authors: DT
authors: Berg
authors: Martin S
authors: MS
authors: Cramer
authors: George E
authors: GE
authors: Sandusky
authors: Timothy A
authors: TA
authors: Sutton
authors: David P
authors: DP
authors: Basile
authors: Brian W
authors: BW
authors: Grinnell
authors: Matthias
authors: M
authors: Clauss
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D018180:Thrombomodulin / Q000627:therapeutic use*; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse