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Figure 3 Diacylglycerol (DAG) signaling pathway proposed for high-glucose–mediated enhanced production of extracellular matrix (ECM) proteins in fibroblasts. High glucose can affect the manner in which fibroblasts respond to angiotensin II. Angiotensin II AT1 receptor levels increase in cells treated with high glucose. The stimulation of AT1 receptors increases the intracellular concentration of DAG. The enzyme in charge of the interconversion of this messenger DAG kinase (DAGK) favors the synthesis of other lipid mediators, which can enter the pathway for the synthesis of dihydroacetone, increase reactive oxygen species, and stimulate protein kinase C (PKC)-beta and/or protein kinase A (PKA). Dihydroacetone can also generate DAG via the action of phosphatidic acid phosphatase (PAP). There also may be protein kinase-independent effects mediated via AT1 receptors, which may alter the production and/or activity of matrix metalloproteinases (MMPs) or other ECM-related genes. Phosphofructokinase (PFK₁) is a rate-limiting enzyme involved in the hexosamine pathway. GLUT-1 = glucose transporter-1; MAPK = mitogen-activated protein kinase; NF-B = nuclear factor kappa B; PLCß = phospholipase C beta.