Korean J Intern Med.  2016 Jan;31(1):116-124. 10.3904/kjim.2016.31.1.116.

Angiotensin III increases monocyte chemoattractant protein-1 expression in cultured human proximal tubular epithelial cells

Affiliations
  • 1Division of Nephrology, Department of Internal Medicine, College of Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea.
  • 2Division of Nephrology, Department of Internal Medicine, College of Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu, Korea. dr52916@catholic.ac.kr
  • 3Renal Research Laboratory, Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • 4Department of Medicine, Stony Brook University of New York, Stony Brook, NY, USA.

Abstract

BACKGROUND/AIMS
We investigated whether angiotensin III (Ang III) is involved in monocyte recruitment through regulation of the chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured human proximal tubular epithelial cells (HK-2 cells).
METHODS
We measured MCP-1 levels in HK-2 cells that had been treated with various concentrations of Ang III and Ang II type-1 (AT1) receptor antagonists at various time points. The phosphorylation states of p38, c-Jun N-terminal kinases (JNK), and extracellular-signal-regulated kinases were measured in Ang III-treated cells to explore the mitogen-activated protein kinase (MAPK) pathway. MCP-1 levels in HK-2 cell-conditioned media were measured after pre-treatment with the transcription factor inhibitors curcumin or pyrrolidine dithiocarbamate.
RESULTS
Ang III increased MCP-1 protein production in dose- and time-dependent manners in HK-2 cells, which was inhibited by the AT1 receptor blocker losartan. p38 MAPK activity increased significantly in HK-2 cells exposed to Ang III for 30 minutes, and was sustained at higher levels after 60 minutes (p < 0.05). Total phosphorylated JNK protein levels tended to increase 20 minutes after stimulation with Ang III. Pre-treatment with a p38 inhibitor, a JNK inhibitor, or curcumin significantly inhibited Ang III-induced MCP-1 production.
CONCLUSIONS
Ang III increases MCP-1 synthesis via stimulation of intracellular p38 and JNK MAPK signaling activity and subsequent activated protein-1 transcriptional activity in HK-2 cells.

Keyword

Angiotensin III; Kidney tubules; Chemokine CCL2; Mitogen-activated protein kinases; Transcription factors

MeSH Terms

Angiotensin II Type 1 Receptor Blockers/pharmacology
Angiotensin III/*pharmacology
Cell Line
Chemokine CCL2/*metabolism
Dose-Response Relationship, Drug
Epithelial Cells/*drug effects/metabolism
Humans
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
Kidney Tubules, Proximal/*drug effects/metabolism
Phosphorylation
Protein Kinase Inhibitors/pharmacology
Signal Transduction/drug effects
Time Factors
Transcription Factor AP-1/metabolism
Up-Regulation
p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
Angiotensin II Type 1 Receptor Blockers
Angiotensin III
Chemokine CCL2
Protein Kinase Inhibitors
JNK Mitogen-Activated Protein Kinases
Transcription Factor AP-1
p38 Mitogen-Activated Protein Kinases
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