GLUCOSE-INDUCED DOWN-REGULATION OF ANGIOTENSIN-II AND ARGININE VASOPRESSIN RECEPTORS IN CULTURED RAT AORTIC VASCULAR SMOOTH-MUSCLE CELLS - ROLE OF PROTEIN-KINASE-C

Early diabetes mellitus is characterized by impaired responses to pressor hormones and pressor receptor downregulation. The present study examined the effect of elevated extracellular glucose concentrations on angiotensin II (AII) and arginine vasopressin (AVP) receptor kinetics in cultured rat vascular smooth muscle cells (VSMC). Scatchard analysis of[H-3]AVP and I-125-AII binding to confluent VSMC showed that high glucose concentrations (20 mM) similarly depressed AVP and All surface receptor B(max) but did not influence receptor K(d). This receptor downregulation was not reproduced by osmotic control media containing either L-glucose or mannitol. Receptor down-regulation was maximal at a glucose concentration of 15-20 mM and required 24-48 h for a maximum effect. Normalization of the extracellular glucose concentration allowed complete recovery of AVP and AII binding within 48 h. Receptor downregulation was associated with depressed AVP and AII-stimulated intracellular signaling and cell contraction. High glucose concentrations induced a sustained activation of protein kinase C (PKC) in VSMC, which was prevented by coincubation with H-7. H-7 also markedly attenuated glucose-induced downregulation of AVP and All receptors on VSMC. This study demonstrates a novel cellular mechanism whereby high extracellular glucose concentrations directly and independently downregulate pressor hormone receptors and their function on vascular tissue via glucose-stimulated PKC activation.