Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes

Young Sun Kang, Yun Gyu Park, Bo Kyung Kim, Sang Youb Han, Yi Hwa Jee, Kum Hyun Han, Mi Hwa Lee, Hye Kyoung Song, Dae-Ryong Cha, Shin Wook Kang, Dae Suk Han

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Abstract

Angiotensin II (Ang-II) and vascular endothelial growth factor (VEGF) have an important role in the pathogenesis of diabetic nephropathy, but the signaling cascade of VEGF regulation in response to Ang-II in podocytes is largely unknown. In these experiments, we looked at the effect of Ang-II on the production of VEGF, and investigated whether VEGF production depends on the p38 mitogen activated protein kinase (MAPK) pathway in cultured mouse podocytes. Incubation of podocytes with Ang-II induced a rapid increase in VEGF mRNA expression and protein synthesis as well as its transcriptional activity in an Ang-II dose-dependent manner. To further define the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors involved in Ang-II-mediated VEGF synthesis, the effects of selective AT1 and AT2 receptor antagonists were evaluated. Prior treatment with losartan significantly inhibited VEGF mRNA and protein synthesis induced by Ang-II, which suggests that the AT1 receptor is involved in Ang-II-mediated VEGF synthesis. Furthermore, stimulation of the cells with Ang-II increased both phosphorylation of p38 MAPK and MAP kinase kinase 3/6 (MKK3/6). Additionally, Ang-II enhanced the DNA binding activity to cAMP response element binding protein (CREB) and phosphorylation of CREB. In addition, to investigate the role of p38 MAPK in Ang-II-induced VEGF synthesis, podocytes were pretreated with or without the p38 MAPK inhibitor, SB203580 for 24 h to observe whether Ang-II-mediated VEGF synthesis was inhibited by blocking p38 MAPK. The addition of SB203580 led to a marked inhibition of the increased VEGF mRNA and protein production induced by Ang-II in a dose-dependent manner. Taken together, these results suggest that Ang-II stimulates the synthesis of VEGF in podocytes and the production of VEGF induced by Ang-II is mediated, in part, through the activation of the p38 MAPK pathway.

Original languageEnglish
Pages (from-to)377-388
Number of pages12
JournalJournal of Molecular Endocrinology
Volume36
Issue number2
DOIs
Publication statusPublished - 2006 Apr 1

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Podocytes
p38 Mitogen-Activated Protein Kinases
Angiotensin II
Vascular Endothelial Growth Factor A
MAP Kinase Kinase Kinase 3
Cyclic AMP Response Element-Binding Protein
Angiotensin Type 1 Receptor
Messenger RNA
Phosphorylation
Angiotensin II Type 1 Receptor Blockers
Proteins
Losartan
Diabetic Nephropathies
Protein Kinase Inhibitors

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes. / Kang, Young Sun; Park, Yun Gyu; Kim, Bo Kyung; Han, Sang Youb; Jee, Yi Hwa; Han, Kum Hyun; Lee, Mi Hwa; Song, Hye Kyoung; Cha, Dae-Ryong; Kang, Shin Wook; Han, Dae Suk.

In: Journal of Molecular Endocrinology, Vol. 36, No. 2, 01.04.2006, p. 377-388.

Research output: Contribution to journalArticle

Kang, Young Sun ; Park, Yun Gyu ; Kim, Bo Kyung ; Han, Sang Youb ; Jee, Yi Hwa ; Han, Kum Hyun ; Lee, Mi Hwa ; Song, Hye Kyoung ; Cha, Dae-Ryong ; Kang, Shin Wook ; Han, Dae Suk. / Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes. In: Journal of Molecular Endocrinology. 2006 ; Vol. 36, No. 2. pp. 377-388.
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abstract = "Angiotensin II (Ang-II) and vascular endothelial growth factor (VEGF) have an important role in the pathogenesis of diabetic nephropathy, but the signaling cascade of VEGF regulation in response to Ang-II in podocytes is largely unknown. In these experiments, we looked at the effect of Ang-II on the production of VEGF, and investigated whether VEGF production depends on the p38 mitogen activated protein kinase (MAPK) pathway in cultured mouse podocytes. Incubation of podocytes with Ang-II induced a rapid increase in VEGF mRNA expression and protein synthesis as well as its transcriptional activity in an Ang-II dose-dependent manner. To further define the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors involved in Ang-II-mediated VEGF synthesis, the effects of selective AT1 and AT2 receptor antagonists were evaluated. Prior treatment with losartan significantly inhibited VEGF mRNA and protein synthesis induced by Ang-II, which suggests that the AT1 receptor is involved in Ang-II-mediated VEGF synthesis. Furthermore, stimulation of the cells with Ang-II increased both phosphorylation of p38 MAPK and MAP kinase kinase 3/6 (MKK3/6). Additionally, Ang-II enhanced the DNA binding activity to cAMP response element binding protein (CREB) and phosphorylation of CREB. In addition, to investigate the role of p38 MAPK in Ang-II-induced VEGF synthesis, podocytes were pretreated with or without the p38 MAPK inhibitor, SB203580 for 24 h to observe whether Ang-II-mediated VEGF synthesis was inhibited by blocking p38 MAPK. The addition of SB203580 led to a marked inhibition of the increased VEGF mRNA and protein production induced by Ang-II in a dose-dependent manner. Taken together, these results suggest that Ang-II stimulates the synthesis of VEGF in podocytes and the production of VEGF induced by Ang-II is mediated, in part, through the activation of the p38 MAPK pathway.",
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AU - Kang, Young Sun

AU - Park, Yun Gyu

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AU - Han, Sang Youb

AU - Jee, Yi Hwa

AU - Han, Kum Hyun

AU - Lee, Mi Hwa

AU - Song, Hye Kyoung

AU - Cha, Dae-Ryong

AU - Kang, Shin Wook

AU - Han, Dae Suk

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N2 - Angiotensin II (Ang-II) and vascular endothelial growth factor (VEGF) have an important role in the pathogenesis of diabetic nephropathy, but the signaling cascade of VEGF regulation in response to Ang-II in podocytes is largely unknown. In these experiments, we looked at the effect of Ang-II on the production of VEGF, and investigated whether VEGF production depends on the p38 mitogen activated protein kinase (MAPK) pathway in cultured mouse podocytes. Incubation of podocytes with Ang-II induced a rapid increase in VEGF mRNA expression and protein synthesis as well as its transcriptional activity in an Ang-II dose-dependent manner. To further define the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors involved in Ang-II-mediated VEGF synthesis, the effects of selective AT1 and AT2 receptor antagonists were evaluated. Prior treatment with losartan significantly inhibited VEGF mRNA and protein synthesis induced by Ang-II, which suggests that the AT1 receptor is involved in Ang-II-mediated VEGF synthesis. Furthermore, stimulation of the cells with Ang-II increased both phosphorylation of p38 MAPK and MAP kinase kinase 3/6 (MKK3/6). Additionally, Ang-II enhanced the DNA binding activity to cAMP response element binding protein (CREB) and phosphorylation of CREB. In addition, to investigate the role of p38 MAPK in Ang-II-induced VEGF synthesis, podocytes were pretreated with or without the p38 MAPK inhibitor, SB203580 for 24 h to observe whether Ang-II-mediated VEGF synthesis was inhibited by blocking p38 MAPK. The addition of SB203580 led to a marked inhibition of the increased VEGF mRNA and protein production induced by Ang-II in a dose-dependent manner. Taken together, these results suggest that Ang-II stimulates the synthesis of VEGF in podocytes and the production of VEGF induced by Ang-II is mediated, in part, through the activation of the p38 MAPK pathway.

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