Protein kinase C (PKC) is a family of protein kinase enzymes with 15 isoforms that are involved in the regulation of protein function. Nine of these 15 PKC isoforms are activated by a lipid second messenger, diacylglycerol. Elevated intracellular glucose increases diacylglycerol levels in a variety of diabetic target tissues, including arterial smooth muscle cells and cardiomyocytes, by de novo synthesis. Hyperglycemia primarily activates the β and δ isoforms of PKC, but increases in activity of several other isoforms have also been found. These PKC isoforms can also be activated by intracellular ROS in the absence of diacylglycerol or Ca2+.
The regulatory domain of these PKC isoforms contains two pairs of zinc fingers with six cysteine residues and two zinc atoms, which can be oxidized by intracellular ROS. Oxidation alters zinc-finger conformation and activates PKC. Intracellular hyperglycemia activates PKC in retina and glomeruli of diabetic animals. In contrast to other complication-prone tissues, total PKC activity is reduced in the peripheral nerve of diabetic animals. Schwann cell PKCα activity is reduced, while vascular wall PKCβII activity is increased.
