Angiotensin II-induced MMP-2 activity and MMP-14 and basigin protein expression are mediated via the angiotensin ii receptor type 1-mitogen-activated protein kinase 1 pathway in retinal pigment epithelium: Implications for age-related macular degeneration

Marianne Pons, Scott W. Cousins, Oscar Alcazar, Gary E. Striker, Maria E. Marin-Castaño

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Accumulation of various lipid-rich extracellular matrix (ECM) deposits under the retinal pigment epithelium (RPE) has been observed in eyes with age-related macular degeneration (AMD). RPE-derived matrix metalloproteinase (MMP)-2, MMP-14, and basigin (BSG) are major enzymes involved in the maintenance of ECM turnover. Hypertension (HTN) is a systemic risk factor for AMD. It has previously been reported that angiotensin II (Ang II), one of the most important hormones associated with HTN, increases MMP-2 activity and its key regulator, MMP-14, in RPE, inducing breakdown of the RPE basement membrane, which may lead to progression of sub-RPE deposits. Ang II exerts most of its actions by activating the mitogen-activated protein kinase (MAPK) signaling pathway. Herein is explored the MAPK signaling pathway as a potential key intracellular modulator of Ang II-induced increase in MMP-2 activity and MMP-14 and BSG protein expression. It was observed that Ang II stimulates phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK in RPE cells and ERK/p38 and Jun N-terminal kinase (JNK) in mice. These effects were mediated by Ang II type 1 receptors. Blockade of ERK or p38 MAPK abrogated the increase in MMP-2 activity and MMP-14 and BSG proteins in ARPE-19 cells. A better understanding of the molecular events by which Ang II induces ECM dysregulation is of critical importance to further define its contribution to the progression of sub-RPE deposits in AMD patients with HTN.

Original languageEnglish (US)
Pages (from-to)2665-2681
Number of pages17
JournalAmerican Journal of Pathology
Volume178
Issue number6
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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