High glucose inhibits cytosolic calcium signaling in cultured rat mesangial cells.
Glomerular vasodilatation in the early stages of type I diabetes mellitus apparently results from arteriolar insensitivity to vasoconstrictors. Since cytosolic free calcium ([Ca2+]i) is a major signaling mechanism for smooth muscle contraction, we studied whether growth of smooth muscle-like rat glomerular mesangial cells in media with high glucose concentration affects [Ca2+]i responses to vasoconstrictors. In cells grown for five days in 22 mM glucose, we observed blunted responsiveness to three structurally unrelated vasoconstrictors that elevate [Ca2+]i via a phospholipase C-dependent mechanism, angiotensin II, prostaglandin F2 alpha, and arginine vasopressin. Inhibition of [Ca2+]i responses was not due to an osmotic effect of high glucose, since it was not mimicked by hypertonic mannitol. While the size of intracellular Ca2+ pools was unaffected by elevated glucose, Na+/Ca2+ exchange was markedly inhibited, thus ruling out both impaired filling of Ca2+ stores and enhanced counter-regulatory mechanisms. Impaired myoinositol transport or intracellular sorbitol accumulation were not responsible for the effects of high glucose, since supplementation of media with myo-inositol or with the aldose reductase inhibitor. Alcon 1576, failed to reverse insensitivity to vasoconstrictors. On the other hand, down-regulation or pharmacological inhibition of protein kinase C completely reversed the effects of high glucose, thus indicating involvement of this signal transduction pathway. These data suggest a possible intracellular mechanism for the impaired vascular sensitivity underlying early renal hemodynamic changes in diabetes mellitus.
Menè
P
P
Dipartimento di Medicina Sperimentale, Cattedra di Endocrinologia e Medicina Costiuzionale, University La Sapienza, Rome, Italy.
Pugliese
G
G
Pricci
F
F
Di Mario
U
U
Cinotti
G A
GA
Pugliese
F
F
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology; D005920:Glomerular Mesangium / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D007476:Ionophores; D001127:Arginine Vasopressin; D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium