Aldosterone Upregulates Connective Tissue Growth Factor Gene Expression via p38 MAPK Pathway and Mineralocorticoid Receptor in Ventricular Myocytes.
10.3346/jkms.2004.19.6.805
- Author:
Young Sam LEE
1
;
Jeong A KIM
;
Koung Li KIM
;
Hyung Suk JANG
;
Jeong Min KIM
;
Jae Young LEE
;
In Soon SHIN
;
Jung Sun LEE
;
Wonhee SUH
;
Jin Ho CHOI
;
Eun Seok JEON
;
Jonghoe BYUN
;
Duk Kyung KIM
Author Information
1. Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea. dkkim@smc.samsung.co.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Connective Tissue Growth Factor;
Aldosterone;
Mitogen-activated Protein Kinase p38;
Spirono-lactone;
Receptor, Mineralocorticoid
- MeSH:
Aldosterone/*pharmacology;
Animals;
Cells, Cultured;
Dose-Response Relationship, Drug;
Gene Expression Regulation/drug effects/physiology;
Heart Ventricles/drug effects/embryology/metabolism;
Immediate-Early Proteins/*metabolism;
Intercellular Signaling Peptides and Proteins/*metabolism;
Myocytes, Cardiac/*drug effects/*metabolism;
Rats;
Receptors, Mineralocorticoid/*metabolism;
Research Support, Non-U.S. Gov't;
Signal Transduction/drug effects/physiology;
Spironolactone/pharmacology;
Up-Regulation/drug effects/physiology;
p38 Mitogen-Activated Protein Kinases/*metabolism
- From:Journal of Korean Medical Science
2004;19(6):805-811
- CountryRepublic of Korea
- Language:English
-
Abstract:
The effect of aldosterone on connective tissue growth factor (CTGF) was examined in rat embryonic ventricular myocytes. Upon aldosterone treatment, CTGF expression was significantly increased in a dose and time-dependent manner. To explore the molecular mechanism for this upregulation, we examined the role of mineralocorticoid receptor. Pre-treatment of an antagonist (spironolactone) at 5-fold excess of aldosterone blocked the CTGF induction by aldosterone, suggesting that the upregulation was mediated by mineralocorticoid receptor. Aldosterone treatment resulted in activation of ERK1/2, p38 MAPK, and JNK pathways with a more transient pat-tern in p38 MAPK. Blocking studies using pre-treatment of the inhibitor of each path-way revealed that p38 MAPK cascade may be important for aldosterone-mediated CTGF upregulation as evidenced by the blocking of CTGF induction by SB203580 (p38 MAPK inhibitor), but not by PD098059 (ERK1/2 inhibitor) and JNK inhibitor I. Interestingly, JNK inhibitor I and PD098059 decreased the basal level of CTGF expression. On the other hand, pre-treatment of spironolactone abrogated the p38 MAPK activation, indicating that mineralocorticoid receptor mechanism is linked to p38 MAPK pathway. Taken together, our findings suggest that aldosterone induces CTGF expression via both p38 MAPK cascade and mineralocorticoid receptor and that cross-talk exists between the two pathways.
