Involvement of RAGE, MAPK and NF‐κB pathways in AGEs‐induced MMP‐9 activation in HaCaT keratinocytes

Abstract

Advanced glycation end products (AGEs) exert divergent effects on the pathogenesis of diabetes complications. Excessive expression of matrix metalloproteinases-9 (MMP-9) is deleterious to the cutaneous wound-healing process in the context of diabetes. However, the effect of AGEs on MMP-9 induction in skin cells and the exact molecular mechanisms involved are still poorly understood. In this study, we investigated the effect of AGEs on the production of MMP-9 in HaCaT keratinocytes and characterized the signal transduction pathways activated by AGEs that are involved in MMP-9 regulation. We showed that AGE-BSA increased MMP-9 expression in HaCaT cells at both the protein and mRNA levels. The stimulatory effect of AGE-BSA on MMP-9 was attenuated by inhibitors of extracellular-signal-regulated kinase (ERK1/2, U0126), p38 mitogen-activated protein kinase (MAPK, SB203580) and NF-κB, but not c-Jun N-terminal kinase. Furthermore, receptor for advanced glycation end products (RAGE) was expressed in keratinocytes, and incubation with AGE-BSA resulted in a significant upregulation of RAGE expression in a dose-dependent manner. Silencing of the RAGE gene prevented AGE-BSA-induced MMP-9 activation and the phosphorylation of ERK1/2 and p38 MAPK. We also observed the involvement of NF-κB in AGE-BSA-induced MMP-9 activation, which was not blocked by U0126 and SB203580. These results suggest that AGEs may play an important role in the impairment of diabetic wound healing by upregulating MMP-9 expression in keratinocytes via the RAGE, ERK1/2 and p38 MAPK pathways; activation of NF-κB is also involved in this process. These pathways may represent potential targets for drug interventions to improve diabetic wound healing, a process in which MMP-9 plays a critical role.

The Mechanisms of Inhibition of Advanced Glycation End Products Formation through Polyphenols in Hyperglycemic Condition

“…It has been reported that AGE-RAGE complex increased TNF-α and MMPs and retarded the wound healing process in diabetic mice. In contrast, the inhibition of AGE-RAGE formation by blocking RAGE resulted in faster wound repair and regeneration [40]. Similarly, the presence of AGE-RAGE complex on fibroblasts reduced the formation of collagen as a necessary compound for wound repairing [41].…”

S100a8/a9 Released by CD11b + Gr1 + Neutrophils Activates Cardiac Fibroblasts to Initiate Angiotensin II–Induced Cardiac Inflammation and Injury

“…S100a8/ a9-RAGE predominantly influences mitogen-activated protein kinase activation and NF-κB signaling. 36,37 We detected significant expression changes in multiple cytokines and chemokines, including CXCL1/2, CCL2, CCL3, CCL5, IL-1β, IL-6, IL-12, and TNF-α. These data are supported by previous studies showing that mitogen-activated protein kinase and NF-κB signaling pathways modulate the release of chemokines and cytokines.…”

Targeting of Receptor for Advanced Glycation End Products Suppresses Cyst Growth in Polycystic Kidney Disease

“…RAGE is a transmembrane receptor and mediates activation of intracellular signal transduction pathways after binding diverse ligands such as AGEs, high mobility group box 1 protein (HMGB1), and S100/calgranulins (12,13). Activation of RAGE triggers intracellular signaling that promotes the proinflammatory tran-scriptional factor NF-B (13,14) and the mitogen-activated protein kinase (MAPK) pathway (15,16). Given the recent studies reporting that AGEs and RAGE are involved in diabetic nephropathy, several methods have been developed to cure chronic kidney disease by interfering with the pathophysiological effect of AGE (12).…”