Aldosterone induces collagen synthesis via activation of extracellular signal-regulated kinase 1 and 2 in renal proximal tubules.
OBJECTIVE
Aldosterone plays a crucial role in renal fibrosis by inducing mesangial cell proliferation and promoting collagen synthesis in renal fibroblasts. However, renal proximal tubule involvement in aldosterone-induced collagen synthesis has not yet been identified. The aim of this study was to examine the potential role of aldosterone in collagen expression and its possible mineralocorticoid receptor (MR)-dependent pathway, mediated by activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cultured human renal proximal tubular epithelial (HKC) cells.


METHODS
After HKC cells were stimulated by aldosterone with different concentrations for various time and periods, the gene expression and protein synthesis of collagen I, II, III and IV were measured by real-time polymerase chain reaction and western blot, respectively. ERK1/2 activation, alpha-smooth muscle actin (alpha-SMA), and E-cadherin were also detected by western blot.


RESULTS
Aldosterone can increase ERK1/2 phosphorylation of human renal proximal tubular epithelial cells in a time- and dose-dependent manner. Although aldosterone had no effect on collagen I and II expression, it increased expression of alpha-SMA and collagen III and IV and decreased that of E-cadherin in HKC cells after 48 h. These effects could be prevented by a ERK pathway inhibitor, U0126, or by a selective MR antagonist, spironolactone.


CONCLUSIONS
The results suggest that aldosterone plays a pivotal role in tubulointerstitial fibrosis by promoting tubular epithelial-mesenchymal transition and collagen synthesis in proximal tubular cells. The process is MR-dependent, and mediated by ERK1/2 mitogen-activated protein kinase pathway.
Xu
Guoshuang
G
Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. xugsh882003@yahoo.com.cn
Liu
An
A
Liu
Xiaowei
X
D000199:Actins / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology*; D005355:Fibrosis; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction; D013148:Spironolactone / Q000494:pharmacology; D013997:Time Factors
D000199:Actins; D002070:Butadienes; D015820:Cadherins; D000451:Mineralocorticoid Receptor Antagonists; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D018161:Receptors, Mineralocorticoid; C113580:U 0126; D013148:Spironolactone; D000450:Aldosterone; D003094:Collagen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3