Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation

Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Masaya Takeda, Tomoko Miyoshi, Jiro Suzuki, Tomoyuki Mukai, Toshio Ogura, Hirofumi Makino

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Abstract

Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume292
Issue number5
DOIs
Publication statusPublished - May 2007

Fingerprint

Bone Morphogenetic Protein 4
Bone Morphogenetic Protein 7
Mesangial Cells
Aldosterone
Cell Proliferation
Mineralocorticoid Receptors
Bone Morphogenetic Proteins
Mitosis
Angiotensin II
Kidney
Bone Morphogenetic Protein 6
Mineralocorticoid Receptor Antagonists
Bone Morphogenetic Protein 2
Angiotensin Type 1 Receptor
MAP Kinase Signaling System
Phosphorylation

Keywords

  • Angiotensin II
  • Kidney
  • Mineralocorticoid

ASJC Scopus subject areas

  • Physiology

Cite this

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title = "Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation",
abstract = "Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.",
keywords = "Angiotensin II, Kidney, Mineralocorticoid",
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T1 - Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation

AU - Otani, Hiroyuki

AU - Otsuka, Fumio

AU - Inagaki, Kenichi

AU - Takeda, Masaya

AU - Miyoshi, Tomoko

AU - Suzuki, Jiro

AU - Mukai, Tomoyuki

AU - Ogura, Toshio

AU - Makino, Hirofumi

PY - 2007/5

Y1 - 2007/5

N2 - Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.

AB - Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.

KW - Angiotensin II

KW - Kidney

KW - Mineralocorticoid

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