Insulin-dependent contractility of glomerular mesangial cells in response to angiotensin II, platelet-activating factor and endothelin is attenuated by prostaglandin E2.
Culture of glomerular mesangial cells in the absence of insulin decreased the degree of contraction of individual cells in response to vasoconstrictive agonists, angiotensin II, platelet-activating factor and endothelin 1, as compared with cells cultured in the presence of insulin (0.7 nM). This change was associated with a decreased sensitivity of the intracellular Ca2+ response to vasoactive agents in fura-2-loaded cells and with an increase in the basal level of prostanoid [prostaglandins (PG) E1 and E2] production estimated by radioimmunoassay. Addition of exogenous PGE2 to insulin-exposed cells decreased the contractile response to that observed in insulin-deficient cells. Inclusion of 8-bromo cyclic AMP had a similar effect. In 45Ca2(+)-release studies it was shown that, in saponin-permeabilized insulin-exposed cells, preincubation with exogenous PGE2 or 8-bromo cyclic AMP decreased the sensitivity of 45Ca2+ release in response to Ins(1,4,5)P3, as demonstrated by an increase in the EC50 (concn. giving half-maximal effect) to 0.182 +/- 0.024 microM and 0.457 +/- 0.031 microM respectively, as compared with untreated permeabilized cells (EC50 0.091 +/- 0.021 microM). A similar decrease in Ins(1,4,5)P3-sensitive 45Ca2+ release was seen in permeabilized cells from insulin-free conditions of culture (EC50 0.20 +/- 0.061 microM). As altered glomerular haemodynamics are found in insulinopaenic diabetic conditions, it is proposed that a decrease in intracellular Ca2+ availability in response to vasoactive agonists and consequent decrease in mesangial-cell contractility contributes to the hyperfiltration seen in this condition.
Dunlop
M E
ME
University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Larkins
R G
RG
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007672:Kidney Cortex / Q000502:physiology; D007700:Kinetics; D008297:Male; D010972:Platelet Activating Factor / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D016232:Endothelins; D007328:Insulin; D010972:Platelet Activating Factor; D000804:Angiotensin II; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D002118:Calcium; D007213:Indomethacin