Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells
| Autor: | Yukihiro Higashiyama, Dilinaer Bolati, Toshimitsu Niwa, Kazuya Shimizu, Hidehisa Shimizu, Fuyuhiko Nishijima |
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| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty p38 mitogen-activated protein kinases General Biochemistry Genetics and Molecular Biology Cell Line Pathogenesis chemistry.chemical_compound Downregulation and upregulation Indoxyl Internal medicine medicine Animals Humans General Pharmacology Toxicology and Pharmaceutics Extracellular Signal-Regulated MAP Kinases Chemokine CCL2 chemistry.chemical_classification Reactive oxygen species Rats Inbred Dahl Monocyte JNK Mitogen-Activated Protein Kinases NF-kappa B NF-κB General Medicine Rats medicine.anatomical_structure Endocrinology Kidney Tubules Biochemistry chemistry Tumor Suppressor Protein p53 Reactive Oxygen Species Indican |
| Zdroj: | Life sciences. 90(13-14) |
| ISSN: | 1879-0631 |
| Popis: | Aims Monocyte chemotactic protein-1 (MCP-1) plays an important role in recruiting monocytes/macrophages to injured tubulointerstitial tissue. The present study examined whether indoxyl sulfate, a uremic toxin, regulates renal expression of MCP-1. Main methods The effect of indoxyl sulfate on the expression of MCP-1 was determined using human proximal tubular cells (HK-2 cells) and following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN + IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH + IS). Key findings DN + IS, DH, and DH + IS rats showed significantly increased mRNA expression of MCP-1 in the kidneys compared with DN rats. DH + IS rats tended to show increased mRNA expression of MCP-1 in the kidneys compared with DH rats. Immunohistochemistry demonstrated the stimulatory effects of indoxyl sulfate on MCP-1 expression and monocyte/macrophage infiltration in the kidneys. Indoxyl sulfate upregulated mRNA and protein expression of MCP-1 in HK-2 cells. Indoxyl sulfate induced activation of ERK, p38, and JNK as well as of NF-κB and p53 in HK-2 cells. An antioxidant, and inhibitors of NF-κB, p53, ERK pathway (MEK1/2), and JNK suppressed indoxyl sulfate-induced mRNA expression of MCP-1 in HK-2 cells. Significance Indoxyl sulfate upregulates renal expression of MCP-1 through production of reactive oxygen species (ROS), and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells. Thus, accumulation of indoxyl sulfate in chronic kidney disease might be involved in the pathogenesis of tubulointerstitial injury through induction of MCP-1 in the kidneys. |
| Databáze: | OpenAIRE |
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