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PMID:17244894

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Citation

Otani, H, Otsuka, F, Inagaki, K, Takeda, M, Miyoshi, T, Suzuki, J, Mukai, T, Ogura, T and Makino, H (2007) Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation. Am. J. Physiol. Renal Physiol. 292:F1513-25

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.

Links

PubMed Online version:10.1152/ajprenal.00402.2006

Keywords

Aldosterone/pharmacology; Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein 7; Bone Morphogenetic Protein Receptors, Type I/metabolism; Bone Morphogenetic Proteins/antagonists & inhibitors; Bone Morphogenetic Proteins/pharmacology; Cell Line; Cell Proliferation/drug effects; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases/metabolism; JNK Mitogen-Activated Protein Kinases/metabolism; Mesangial Cells/cytology; Mice; Mitogen-Activated Protein Kinases/metabolism; Mitosis/drug effects; Phosphorylation/drug effects; Receptors, Mineralocorticoid/antagonists & inhibitors; Signal Transduction/drug effects; Smad6 Protein/metabolism; Spironolactone/analogs & derivatives; Spironolactone/pharmacology; Transforming Growth Factor beta/antagonists & inhibitors; Transforming Growth Factor beta/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BMP2

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0060395: SMAD protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP6

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP6

involved_in

GO:0060395: SMAD protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0072125: negative regulation of glomerular mesangial cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0060395: SMAD protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0045839: negative regulation of mitotic nuclear division

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0043407: negative regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0043401: steroid hormone mediated signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0034504: protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP7

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060395: SMAD protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0034504: protein localization to nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0042326: negative regulation of phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0045839: negative regulation of mitotic nuclear division

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0043401: steroid hormone mediated signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0043407: negative regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0072125: negative regulation of glomerular mesangial cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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