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Title: [The role of MAPK/ERK1/2 signaling pathway in aldosterone stimulated transforming growth factor-beta1 synthesis in renal tubular epithelial cells].
Author: Luo Y, Rui HL, Chen YP.
Journal: Zhonghua Yi Xue Za Zhi; 2006 Nov 28; 86(44):3133-7. PubMed ID: 17313766.
Abstract:
OBJECTIVE: Our previous study have demonstrated that the expression of transforming growth factor-beta1 (TGF-beta1) by HKC could be up-regulated by aldosterone (ALDO) in vitro. The present study was designed to evaluate the role of MAPK/ERK1/2 phosphorylation in mediating the synthesis of TGF-beta1 in renal tubular epithelial cells that was activated by aldosterone. METHODS: The following tests were performed in vitro: (1) HKC were pretreated with different concentrations of specific ERK1/2, JNK and P38 MAPK pathway inhibitors for 4h, then HKC were stimulated with 10(-7) mol/L ALDO for 48 h, finally enzyme-linked immunosorbent assay (ELISA) were performed to detect TGF-beta1 expression; (2) HKC were stimulated with ALDO at different concentrations and times, then western blot assay was performed to detect the expression of phosphorylated and total ERK1/2 in the cell lysate of HKC. (3) HKC which were co-stimulated with 10(-7) mol/L ALDO and different concentrations of spironolactone or specific glucocorticoid hormone receptor inhibitor RU486 for 30min, then western blot assay was performed to detect the expression of phosphorylated and total ERK1/2 in the cell lysate of HKC. RESULTS: (1) the production in 15 and 25 micromol/L U0126 incubated groups was (87 +/- 11) pg/ml and (75 +/- 19) pg/ml respectively, which was significantly decreased compared with that in 10(-7) mol/L ALDO incubated group (P < 0.05), however, the amount of TGF-beta1 in these groups were still significant higher than that in the control group (P < 0.05). The production of TGF-beta1 in the groups which were incubated with SP600125 and SB203580 did not appear significant decrease compared with that in 10(-7) mol/L ALDO incubated group (P > 0.05), the production of TGF-beta1 in these groups was also significant higher than that in the control group (P < 0.05). (2) The Phos/Total ERK1/2 ratio was increased in a dose-dependent manner. After HKC were stimulated with 10(-9) - 10(-7) mol/L ALDO for 30 min. Phos/TotalERK1/2 ratio was 0.67 +/- 0.06 and 0.80 +/- 0.05 respectively, which was significantly increased (vs 0 mol/L ALDO, P < 0.05 or 0.01). The expression of Phos/Total ERK1/2 ratio also had a positive correlations with the production of TGF-beta1 (R = 0.793, P < 0.01). With 10(-7) mol/L ALDO stimulated at different times, the Phos/Total ERK1/2 ratio was also significantly increased (vs 0 h, P < 0.05 or 0.01), which began to be increased and reached the peak at 15 min, the relatively ratio was 0.84 +/- 0.06, and waned till 240 min, and returned to normal level at 360 min. (3) After co-stimulated with 10(-7) mol/L ALDO and different concentration of spironolactone, Phos/TotalERK1/2 ratio was significantly decreased along with the concentrations of spironolactone, the relatively ratio of in 10(-9) - 10(-7) was 0.62 +/- 0.08 and 0.60 +/- 0.04 separately (vs 0 mol/L ALDO, or 0.01), but they were still significantly higher than that in control group (P < 0.05). The Phos/TotalERK1/2 ratio was not changed significantly along with the concentrations of RU486 (P > 0.05). CONCLUSION: The effect of aldosterone in up-regulating the expression of TGF-beta1 in HKC is mediated, at least in part, by MAPK/ERK1/2 pathway. Aldosterone may exert this effect on the conditions of binding to the mineralocorticoid receptor first.

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