Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury

T. Suganami, M. Mukoyama, A. Sugawara, K. Mori, T. Nagae, M. Kasahara, K. Yahata, H. Makino, Y. Fujinaga, Yoshihiro Ogawa, I. Tanaka, K. Nakao

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Abstract

One of major causes of end-stage renal disease is glomerulonephritis, the treatment of which remains difficult clinically. It has already been shown that transgenic mice that overexpress brain natriuretic peptide (BNP), with a potent vasorelaxing and natriuretic property, have ameliorated glomerular injury after subtotal nephrectomy. However, the role of natriuretic peptides in immune-mediated renal injury still remains unknown. Therefore, the effects of chronic excess of BNP on anti-glomerular basement membrane nephritis induced in BNP-transgenic mice (BNP-Tg) were investigated and the mechanisms how natriuretic peptides act on mesangial cells in vitro were explored. After induction of nephritis, severe albuminuria (∼21-fold above baseline), tissue damage, including mesangial expansion and cell proliferation, and functional deterioration developed in nontransgenic littermates. In contrast, BNP-Tg exhibited much milder albuminuria (approximately fourfold above baseline), observed only at the initial phase, and with markedly ameliorated histologic and functional changes. Up-regulation of transforming growth factor-β (TGF-β and monocyte chemoattractant protein-1 (MCP-1), as well as increased phosphorylation of extracellular signal-regulated kinase (ERK), were also significantly inhibited in the kidney of BNP-Tg. In cultured mesangial cells, natriuretic peptides counteracted the effects of angiotensin II with regard to ERK phosphorylation and fibrotic action. Because angiotensin II has been shown to play a pivotal role in the progression of nephritis through induction of TGF-β and MCP-1 that may be ERK-dependent, the protective effects of BNP are likely to be exerted, at least partly, by antagonizing the renin-angiotensin system locally. The present study opens a possibility of a novel therapeutic potential of natriuretic peptides for treating immune-mediated renal injury.

Original languageEnglish
Pages (from-to)2652-2663
Number of pages12
JournalJournal of the American Society of Nephrology
Volume12
Issue number12
Publication statusPublished - 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Nephrology

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    Suganami, T., Mukoyama, M., Sugawara, A., Mori, K., Nagae, T., Kasahara, M., Yahata, K., Makino, H., Fujinaga, Y., Ogawa, Y., Tanaka, I., & Nakao, K. (2001). Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury. Journal of the American Society of Nephrology, 12(12), 2652-2663.