REGULATION OF MESANGIAL CHLORIDE CHANNELS BY INSULIN AND GLUCOSE - ROLE IN DIABETIC NEPHROPATHY

1. In response to vasoactive peptides (e.g. angiotensin II (AngII), va sopressin, endothelin-1, platelet-activating factor), glomerular mesan gial cell contraction is mediated through activation of a Ca2+-depende nt Cl- conductance that, in turn, promotes membrane depolarization and voltage-activated Ca2+ entry. 2. Using patch clamp technology, our la boratory was the first to characterize a candidate Ca2+-dependent, 4pS Cl- channel that is stimulated by vasoactive peptides in cultured rat mesangial cells. In the absence of extracellular insulin, the activat ion of Cl- channels by AngII is abolished. We find that Cl- channel se nsitivity to intracellular Ca2+ and the membrane density of AngII rece ptors is also dependent on the presence of insulin. 3. Our studies als o show that high extracellular glucose interferes with mesangial cell IP3 generation and Cl- channel stimulation. importantly, we find that the insulin-dependency of Cl- channels occurs within the range of plas ma insulin concentrations observed in normal, obese, hypertensive and diabetic humans (i.e. 1-100 mu U/mL). Similarly, normal regulation of Cl- channel activity is also modulated by glucose concentrations commo nly observed in the plasma of diabetic humans (5-30 mmol/L). 4. There is substantial evidence, both in diabetic humans and animal models, th at the provision of insulin and improved glycaemic control corrects or prevents glomerular hyperfiltration. The requirement for normal insul in and glucose levels, for the proper regulation of the 4pS Cl- channe l, provides a mechanism for impaired Ca2+ uptake and contraction obser ved in glomerular mesangial cells in association with insulin deficien cy and hyperglocaemia.