Cytoprotective effects of adrenomedullin in glomerular cell injury: Central role of cAMP signaling pathway

Eduardo N. Chini, Claudia C.S. Chini, Chad Bolliger, Michihisa Jougasaki, Joseph P. Grande, John C. Burnett, Thomas P. Dousa

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

Activation of cAMP signaling pathway was shown to inhibit some pathobiologic processes in mesangial cells (MC). We investigated whether adrenomedullin (ADM), a potent agonist of adenylate cyclase, is synthesized in MC and whether it can, via cAMP, suppress the generation of reactive oxygen metabolites (ROM) and proliferation of cells in glomeruli. With the use of an immunohistologic technique ADM was detected in mesangial and microvascular areas of rat glomeruli. MC grown in primary culture synthesized ADM, and the synthesis was stimulated by TNFα and IL-1β but not by PDGF and EGF. ADM inhibited ROM generation in MC dose-dependently and caused in situ activation of protein kinase A (pKA). In macrophages (cell line J774) ROM generation was about four times higher than in MC and was inhibited by ADM in a similar way as in MC. The rate of MC proliferation, measured by [3H]-incorporation, and the activity of mitogen-activated protein kinase (MAPK) stimulated by PDGF and EGF were dose-dependently inhibited by ADM; the maximum inhibition (at 10 nM ADM) was about -80%. Mitogenesis of MC and MAPK activity when stimulated to a similar extent by endothelin (ET-1) was inhibited by ADM to a significantly (P < 0.01) lesser degree (-30%). Further, ADM inhibited PDGF-stimulated mitogenesis and activation of MAPK in cultured vascular smooth muscle cells (VSMC). The inhibition of PDGF-activated MAPK by ADM in VSMC was reversed by the protein kinase A (PKA) inhibitor, H89. Taken together, results indicate that adrenomedullin (ADM) generated in mesangial cells (MC) can suppress, via activation of the cAMP-protein kinase A (PKA) signaling pathway, reactive oxygen metabolites (ROM) generation in MC and infiltrating macrophages as well as mitogen-activated protein kinase (MAPK)-mediated mitogenesis in MC and vascular smooth muscle cells (VSMC). We suggest that intraglomerular ADM may serve as a cytoprotective autacoid that suppresses pathobiologic processes evoked by immuno-inflammatory injury of glomeruli.

Original languageEnglish (US)
Pages (from-to)917-925
Number of pages9
JournalKidney international
Volume52
Issue number4
DOIs
StatePublished - Jan 1 1997

Keywords

  • Adrenomedullin
  • Injury
  • Mesangial cells
  • Reactive oxygen metabolites
  • cAMP-PKA signaling pathway

ASJC Scopus subject areas

  • Nephrology

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