Aldosterone upregulates connective tissue growth factor gene expression via p38 MAPK pathway and mineralocorticoid receptor in ventricular myocytes.
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 pattern in p38 MAPK. Blocking studies using pretreatment of the inhibitor of each pathway 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, pretreatment 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.
Lee
Young-Sam
YS
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kim
Jeong-A
JA
Kim
Koung Li
KL
Jang
Hyung-Suk
HS
Kim
Jeong-Min
JM
Lee
Jae-Young
JY
Shin
In-Soon
IS
Lee
Jung-Sun
JS
Suh
Wonhee
W
Choi
Jin-Ho
JH
Jeon
Eun-Seok
ES
Byun
Jonghoe
J
Kim
Duk-Kyung
DK
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018161:Receptors, Mineralocorticoid; D055513:Connective Tissue Growth Factor; D013148:Spironolactone; D000450:Aldosterone; D048051:p38 Mitogen-Activated Protein Kinases