Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice

Raja Shekhar Gangaraju, Akanksha Gupta, Abby Marin, Jessica Friedrich, Antje Willuweit, David T. Berg, Martin S. Cramer, George E. Sandusky, Timothy A. Sutton, David P. Basile, Brian W. Grinnell, Matthias Clauss

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume302
Issue number6
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

Fingerprint

Thrombomodulin
Transgenic Mice
Inflammation
Chronic Renal Insufficiency
Chemokines
Blood Vessels
Kidney
Endothelial Cells
Albuminuria
Vascular System Injuries
Kidney Diseases
Subcutaneous Injections
Protein C
Acute Kidney Injury
Endothelium
Monocytes
Leukocytes
Down-Regulation
Pathology
Phenotype

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice. / Gangaraju, Raja Shekhar; Gupta, Akanksha; Marin, Abby; Friedrich, Jessica; Willuweit, Antje; Berg, David T.; Cramer, Martin S.; Sandusky, George E.; Sutton, Timothy A.; Basile, David P.; Grinnell, Brian W.; Clauss, Matthias.

In: American Journal of Physiology - Renal Physiology, Vol. 302, No. 6, 01.03.2012.

Research output: Contribution to journalArticle

Gangaraju, RS, Gupta, A, Marin, A, Friedrich, J, Willuweit, A, Berg, DT, Cramer, MS, Sandusky, GE, Sutton, TA, Basile, DP, Grinnell, BW & Clauss, M 2012, 'Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice', American Journal of Physiology - Renal Physiology, vol. 302, no. 6. https://doi.org/10.1152/ajprenal.00558.2011
Gangaraju, Raja Shekhar ; Gupta, Akanksha ; Marin, Abby ; Friedrich, Jessica ; Willuweit, Antje ; Berg, David T. ; Cramer, Martin S. ; Sandusky, George E. ; Sutton, Timothy A. ; Basile, David P. ; Grinnell, Brian W. ; Clauss, Matthias. / Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice. In: American Journal of Physiology - Renal Physiology. 2012 ; Vol. 302, No. 6.
@article{97051405e34e48008b953188614a38ee,
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.",
author = "Gangaraju, {Raja Shekhar} and Akanksha Gupta and Abby Marin and Jessica Friedrich and Antje Willuweit and Berg, {David T.} and Cramer, {Martin S.} and Sandusky, {George E.} and Sutton, {Timothy A.} and Basile, {David P.} and Grinnell, {Brian W.} and Matthias Clauss",
year = "2012",
month = "3",
day = "1",
doi = "10.1152/ajprenal.00558.2011",
language = "English (US)",
volume = "302",
journal = "American Journal of Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice

AU - Gangaraju, Raja Shekhar

AU - Gupta, Akanksha

AU - Marin, Abby

AU - Friedrich, Jessica

AU - Willuweit, Antje

AU - Berg, David T.

AU - Cramer, Martin S.

AU - Sandusky, George E.

AU - Sutton, Timothy A.

AU - Basile, David P.

AU - Grinnell, Brian W.

AU - Clauss, Matthias

PY - 2012/3/1

Y1 - 2012/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863403541&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863403541&partnerID=8YFLogxK

U2 - 10.1152/ajprenal.00558.2011

DO - 10.1152/ajprenal.00558.2011

M3 - Article

VL - 302

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 1931-857X

IS - 6

ER -