Regulation of B-2-kinin receptors by glucose in vascular smooth muscle cells

The development of vascular disease is accelerated in hyperglycemic states. Vascular injury plays a pivotal role in the progression of atherosclerotic vascular disease in diabetes, which is characterized by increased vascular smooth muscle cell (VSMC) proliferation and extracellular matrix accumulat ion. We previously reported that diabetes alters the activity of the kallik rein- kinin system and results in the upregulation of kinin receptors in th e vessel wall. To determine whether glucose can directly influence the regu lation of kinin receptors, the independent effect of high glucose (25 mM) o n B-2-kinin receptors (B2KR) in VSMC was examined. A threefold increase in B2KR protein levels and a 40% increase in B2KR surface receptors were obser ved after treatment with high glucose after 24 h. The mRNA levels of B2KR w ere also significantly increased by high glucose as early as 4 h later. To elucidate the cellular mechanisms by which glucose regulates B2KR, we exami ned the role of protein kinase C (PKC). High glucose increased total PKC ac tivity and resulted in the translocation of conventional PKC isoforms (beta (1) and beta (2)), novel (epsilon), and atypical (zeta) PKC isoforms into the membrane. Inhibition of PKC activity prevented the increase in B2KR lev els induced by ambient high glucose. These findings provide the first evide nce that glucose regulates the expression of beta (2) receptors in VSMC and provide a rationale to further study the interaction between glucose and k inins on the pathogenesis of atherosclerotic vascular disease in diabetes.