Site-Specific Inhibition of Glomerulonephritis Progression by Targeted Delivery of Dexamethasone to Glomerular Endothelium

Ásgeirsdóttir, Sigrídur A.; Kamps, Jan A. A. M.; Bakker, Hester I.; Zwiers, Peter J.; Heeringa, Peter; Weide, Karen van der; Goor, Harry van; Petersen, Arjen H.; Morselt, Henriëtte W. M.; Moorlag, Henk E.; Steenbergen, Eric J.; Kallenberg, Cees G. M.; Molema, Grietje

doi:10.1124/mol.107.034140

Cited by 77 publications

(61 citation statements)

References 39 publications

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“…Intense expression of E-selectin (24,25) and activated glomerular endothelial cells (26) have been observed in the kidneys of CKD animal models. Furthermore, circulating E-selectin is a strong predictor of death and cardiovascular events in patients with end-stage renal disease (27,28).…”

Section: Discussionmentioning

confidence: 99%

Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions through Up-regulation of E-selectin

Ito

Osaka

Higuchi

et al. 2010

Journal of Biological Chemistry

148

133

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Cardiovascular disease is a major cause of death in chronic kidney disease (CKD) 2 (1). Atherosclerosis is highly prevalent in patients with severe renal failure and advances more rapidly in individuals with renal dysfunction compared with the general population (2). Reduced kidney function is associated with the risk of cardiovascular events, even when the dysfunction is mild (3).Leukocyte-endothelial interactions play an important role in the development of atherosclerosis (4). Cell adhesion molecules belonging to the immunoglobulin superfamily, such as ICAM-1 (intercellular cell adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1), together with members of the selectin family, including E-selectin, are upregulated to mediate monocyte/macrophage infiltration into atherosclerotic lesions (4, 5).Indoxyl sulfate is a uremic toxin synthesized in the liver from indole, a metabolite of tryptophan produced by the intestinal flora (6). In CKD patients, the serum levels of indoxyl sulfate are increased significantly compared with those in healthy individuals (7), and a number of studies have indicated that indoxyl sulfate accelerates glomerular sclerosis, whereas its accumulation promotes renal failure (8 -10). Other studies also showed that indoxyl sulfate induces endothelial dysfunction by releasing endothelial microparticles (11) and producing reactive oxygen species (ROS) (12). However, its effect on endothelial inflammatory processes such as leukocyte recruitment to vascular endothelium has not been reported.We report for the first time that indoxyl sulfate enhances monocyte adhesion to vascular endothelium through up-regulation of E-selectin and augmentation of oxidative stress in both in vitro and in vivo models. The underlying mechanisms seem to involve activation of JNK and NF-B. Our findings reveal a previously unrecognized molecular link between uremic toxins and cardiovascular diseases. EXPERIMENTAL PROCEDURESReagents-Indoxyl sulfate, N-acetylcysteine, probenecid, RPMI 1640 medium, and Dulbecco's PBS were obtained from Sigma. The JNK phosphorylation inhibitor SP600125, the p38 MAPK phosphorylation inhibitor SB203580, the ERK1/2 inhibitor U0126, and the IB phosphorylation inhibitor BAY11-7082 were purchased from Calbiochem. Recombinant human TNF-␣ was obtained from R&D Systems (Minneapolis, MN). A monoclonal antibody against E-selectin (clone 7A9) was obtained from American Type Culture Collection (Manassas, VA) (13). Antibodies against ICAM-1, VCAM-1, the NF-B p65 subunit, and the phospho-NF-B p65 subunit and a monoclonal blocking antibody against mouse E-selectin (clone UZ4) were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Anti-ERK, anti-phospho-ERK, anti-p38 MAPK, anti-phospho-p38 MAPK, anti-JNK, and anti-phos-* This work was supported in part by Ministry of Education, Science, and Technology Grant-in-aid for Scientific Research 10178102 and special coordination funds, a grant-in-aid from the Ministry of Culture of Japan, a grant from the Ministry of Health, Labor, and We...

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Section: Discussionmentioning

confidence: 99%

Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions through Up-regulation of E-selectin

Ito

Osaka

Higuchi

et al. 2010

Journal of Biological Chemistry

148

133

View full text Add to dashboard Cite

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“…Animals were maintained on mouse chow and tap water ad libitum in a temperature-controlled chamber at 24°C with a 12:12-h light-dark cycle. Induction of anti-glomerular basement membrane (GBM) glomerulonephritis was performed as described previously (2). Mice were euthanized at 2 h. Alternatively, inflammation was systemically induced by intravenous injection of recombinant mouse TNF-␣ (BioSource Europe, Nivelles, Belgium) at a 200-ng dose.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation

Ásgeirsdóttir

Solingen

Kurniati

et al. 2012

American Journal of Physiology-Renal Physiology

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Endothelial cells in different microvascular segments of the kidney have diverse functions and exhibit differential responsiveness to disease stimuli. The responsible molecular mechanisms are largely unknown. We previously showed that during hemorrhagic shock, VCAM-1 protein was expressed primarily in extraglomerular compartments of the kidney, while E-selectin protein was highly induced in glomeruli only (van Meurs M, Wulfert FM, Knol AJ, de Haes A, Houwertjes M, Aarts LPHJ, Molema G. Shock 29: 291–299, 2008). Here, we investigated the molecular control of expression of these endothelial cell adhesion molecules in mouse models of renal inflammation. Microvascular segment-specific responses to the induction of anti-glomerular basement membrane (anti-GBM), glomerulonephritis and systemic TNF-α treatment showed that E-selectin expression was transcriptionally regulated, with high E-selectin mRNA and protein levels preferentially expressed in the glomerular compartment. In contrast, VCAM-1 mRNA expression was increased in both arterioles and glomeruli, while VCAM-1 protein expression was limited in the glomeruli. These high VCAM-1 mRNA/low VCAM-1 protein levels were accompanied by high local microRNA (miR)-126 and Egfl7 levels, as well as higher Ets1 levels compared with arteriolar expression levels. Using miR-reporter constructs, the functional activity of miR-126 in glomerular endothelial cells could be demonstrated. Moreover, in vivo knockdown of miR-126 function unleashed VCAM-1 protein expression in the glomeruli upon inflammatory challenge. These data imply that miR-126 has a major role in the segmental, heterogenic response of renal microvascular endothelial cells to systemic inflammatory stimuli.

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“…Specific targeted delivery of therapeutic agents to kidneys, and even to specific renal cells in the glomeruli or the tubulointerstitium, seems feasible (442)(443)(444)(445)(446)(447) and might open the possibility of using drugs that would otherwise be limited by systemic toxicity. Such approaches may also be combined with contrast agents for non-invasive imaging allowing a ''theranostic'' strategy which is currently mainly being developed for cancer applications.…”

Section: Getting Anti-fibrotic Therapies To the Clinicmentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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Site-Specific Inhibition of Glomerulonephritis Progression by Targeted Delivery of Dexamethasone to Glomerular Endothelium

Cited by 77 publications

References 39 publications

Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions through Up-regulation of E-selectin

Indoxyl Sulfate Induces Leukocyte-Endothelial Interactions through Up-regulation of E-selectin

MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation

Renal Allograft Fibrosis: Biology and Therapeutic Targets

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