K009 Aldosterone plays a role in tissue repair by enhancing MMP-9 activity in immune cells

Background and aim Immune cells are involved in tissue repair by their capacity to infiltrate, to degrade the extracellular matrix and to promote cell proliferation. These immune cells express mineralocorticoid receptors. The aim of this study was to investigate whether aldosterone (Aldo) was able to regulate MMP-9 production of immune cells. In fact, MMP-9 is tightly correlated with extracellular matrix degradation and this step is a preliminary and essential process for tissue repair so that endothelial and vascular muscle cell proliferation can take place. Methods HL-60 (progranulocytic) and THP-1 (promonocytic) cell lines and human blood neutrophils and monocytes were incubated for different times with Aldo (10-7, 10-8, 10-9 M). Cell supernatants were collected and pro-MMP-9 and MMP-9 excretion were analysed by zymography and ELISA. MMP-9 mRNA expression was analysed by RT-PCRq. Results All four cell types increased their pro-MMP-9 and MMP-9 production in response to Aldo. In neutrophil cells type (HL-60 and blood neutrophils) MMP-9 mRNA production was increased 30mn after Aldo addition and two peaks were observed, at 1 h 30 and at 6 hours, whatever the Aldo concentration. With monocyte cell types (THP-1 and blood monocytes) this MMP-9 mRNA increase was maximal at 3 hours. Zymography and ELISA showed increased excretion of pro-MMP-9 and MMP-9 proteins 24 hours after hormone incubation for all four cell types. Western-blotting performed with HL-60 and THP-1 cells showed that ERK1/2 and p38 pathways were stimulated by Aldo. Transduction signal inhibitors of these proteins and of PI3kinase decreased this immune cell activation by Aldo. Conclusion We have demonstrated that Aldo is able to up-regulate pro-MMP-9 and MMP-9 production in immune cells such as neutrophils and monocytes. This phenomenon appears to be PI3K, ERK1/2 and p38 dependent. As these cells play an important role in tissue repair notably by their capacity to degrade extracellular matrix in order to favour cell proliferation and tissue building, it appears that Aldo could be important in this process.