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Am J Physiol Renal Physiol (January 23, 2007). doi:10.1152/ajprenal.00402.2006
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Submitted on October 11, 2006
Accepted on January 21, 2007

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

Hiroyuki Otani1, Fumio Otsuka1*, Kenichi Inagaki2, Masaya Takeda2, Tomoko Miyoshi2, Jiro Suzuki2, Tomoyuki Mukai2, Toshio Ogura2, and Hirofumi Makino2

1 Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan
2 Okayama, Japan; Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan

* To whom correspondence should be addressed. E-mail: fumiotsu{at}md.okayama-u.ac.jp.

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 using mouse mesangial cells, which express mineralocorticoid receptors (MR), angiotensin II (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 a 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 the MR expression. MAPK inhibitors including U0126 and SP600125, but not SB203580, 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 activated 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 crosstalk 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.




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