Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal-regulated kinase activation and renal fibrosis

T. Nagae, K. Mori, M. Mukoyama, M. Kasahara, H. Yokoi, T. Suganami, K. Sawai, T. Yoshioka, M. Koshikawa, Y. Saito, Y. Ogawa, T. Kuwabara, I. Tanaka, A. Sugawara, T. Kuwahara, K. Nakao

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Abstract

Systemic administration of the potent vasodilating peptide adrenomedullin reduces cardiac and renal fibrosis in hypertensive animals. Here, we investigated the effects of kidney-specific adrenomedullin gene delivery in normotensive rats after unilateral ureteral obstruction, an established model of renal tubulointerstitial fibrosis. Overexpression of exogenous adrenomedullin in the renal interstitium following ureteral obstruction significantly prevented fibrosis and proliferation of tubular and interstitial cells. In this model, there is upregulation of connective tissue growth factor (CTGF) mRNA expression and extracellular signal-regulated kinase (ERK) phosphorylation, and adrenomedullin overexpression suppressed both of these activities without altering the blood pressure. In NRK-49F renal fibroblasts, adrenomedullin reduced transforming growth factor-β-induced CTGF and fibronectin mRNA upregulation through the cyclic AMP/protein kinase A signaling pathway, and suppressed ERK phosphorylation and cell proliferation. In the kidneys with an obstructed ureter, adrenomedullin receptor gene expression was upregulated along with cyclic AMP production in kidney slices. The latter effect was partially blocked by a neutralizing antibody to adrenomedullin, indicating that an endogenous peptide-receptor system was activated. Our results show that overexpression of exogenous adrenomedullin in the ureteral-obstructed kidney prevents tubulointerstitial fibrosis and cell proliferation through the cyclic AMP-mediated decrease of CTGF induction and ERK phosphorylation.

Original languageEnglish
Pages (from-to)70-80
Number of pages11
JournalKidney International
Volume74
Issue number1
DOIs
Publication statusPublished - Jul 2008

All Science Journal Classification (ASJC) codes

  • Nephrology

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    Nagae, T., Mori, K., Mukoyama, M., Kasahara, M., Yokoi, H., Suganami, T., Sawai, K., Yoshioka, T., Koshikawa, M., Saito, Y., Ogawa, Y., Kuwabara, T., Tanaka, I., Sugawara, A., Kuwahara, T., & Nakao, K. (2008). Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal-regulated kinase activation and renal fibrosis. Kidney International, 74(1), 70-80. https://doi.org/10.1038/ki.2008.98