Induction of Resistance to Endothelin-1's Biochemical Actions by Elevated Glucose Levels in Retinal Pericytes

Abstract

Because retinal pericytes have contractile properties and are affected by diabetes, we have studied the responsiveness of pericytes to ET-1, a potent vasoconstrictor, in the presence of various concentrations of glucose. Cultured calf retinal pericytes were exposed to glucose levels of 5.5 or 25 mM for up to 8 days. Radioreceptor studies that used [ 125 I]ET-1 showed that pericytes contained high-affinity binding sites with /Q of 3 x 1O~1 0 M, and these binding affinities were unaffected by glucose concentration. Receptor number appears to be elevated, but this increase was NS. Responsiveness of pericytes to ET-1 was studied with respect to stimulation of DAG and IP 3 levels and PKC activities. In contrast to receptor binding, exposure to 25 mM glucose for >6 days blunted pericyte responsiveness to ET-1. The time course of ET-1 stimulation as measured by [ 3 H]glycerol labeling, and IP 3 level showed a 98% increase in [ 3 H]DAG at 10 min and a fourfold increase for IP 3 , respectively. Cells exposed to 25 mM glucose only had a 32% increase for DAG, and no increase for IP 3 was observed. Dose-response studies on the stimulation of [ 3 H]DAG increase showed the range of ET-1's effect to be between 10" 9 and 1 0 7 M. At maximum, cells exposed to 5.5 mM glucose had a 70% increase versus only a 30% increase in those exposed to 25 mM glucose. Similarly, ET-1 only increased the total DAG levels in pericytes exposed to 5.5 mM glucose by 41%. PKC activity also was measured

Cardiac pericytes function as key vasoactive cells to regulate homeostasis and disease

“…Furthermore, retinal PCs' responsiveness to endothelin‐1 was significantly decreased by elevated glucose levels which can affect the cells' contraction. Although our cardiac PCs do not express endothelin‐1 receptors, elevated glucose levels can also cause the cardiac PCs to develop PE resistance [89]. Therefore, the inability of cardiac PCs to contract under hyperglycemic conditions can contribute to the altered hemodynamics and hypertrophy seen in diabetics.…”

Vascular risk factors for optical coherence tomography‐detected macular cysts: The Maastricht Study

“…Importantly, in small retinal vessels the propagated pulsatile load could contribute to basement membrane thickening (de la Rubia et al. 1992), capillary occlusion, dilatation of neighbouring vessels, secretion of growth factors (Resnick et al. 1993) and new vessel formation (Kohner et al.…”