Effect of protein kinase C modulators on the leucocyte Na+/H+ antiport in type 1 (insulin-dependent) diabetic subjects with albuminuria.
It is uncertain why only one third of Type 1 (insulin-dependent) diabetic patients develop nephropathy. One suggestion is the inheritance of a predisposition to essential hypertension. We have previously found elevated Na+/H+ antiport activity and a raised intracellular pH in leucocytes from hypertensive and Type 1 diabetic subjects with albuminuria using a novel double ionophore fluorimetric technique. These changes are not found in Type 1 diabetic subjects without albuminuria. We wished to test the effect of a protein kinase C inhibitor staurosporine (100 nmol/l) on the elevated antiport activity, and the degree of stimulation achieved by exogenous diacyl glycerol. Raised leucocyte Na+/H+ antiport activity of Type 1 diabetic subjects with albuminuria (73.8 +/- 17.2 mmol.l-1.min-1) was restored to normal levels with staurosporine (54.9 +/- 17.9 mmol.l-1.min-1, p less than 0.001). The leucocyte Na+/H+ antiport activity of diabetic subjects without albuminuria fell significantly also with staurosporine but to a lesser extent (57.3 +/- 11.6 to 50.0 +/- 12.8 mmol/l, p less than 0.003). In contrast, leucocytes from normal control subjects showed no change in antiport activity with staurosporine (54.3 +/- 8.5 to 52.6 +/- 10.4 mmol.l-1.min-1). Dioctanoyl glycerol stimulated the leucocyte Na+/H+ antiport in normal subjects and diabetic patients without albuminuria, with significantly less stimulation in diabetic patients with albuminuria. We conclude that reversal by staurosporine of the elevated Na+/H+ antiport activity in Type 1 diabetic subjects with albuminuria could indicate a role for protein kinase C in activating the antiport. This hypothesis is supported by the reduced stimulation of the antiport by dioctanoyl glycerol in this group of patients.
Ng
L L
LL
Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford, UK.
Simmons
D
D
Frighi
V
V
Garrido
M C
MC
Bomford
J
J
D000419:Albuminuria; D000470:Alkaloids / Q000494:pharmacology*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D002352:Carrier Proteins / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D017923:Sodium-Hydrogen Exchangers; D019311:Staurosporine
D000470:Alkaloids; D000584:Amiloride; D001786:Blood Glucose; D002352:Carrier Proteins; D006442:Glycated Hemoglobin; D007328:Insulin; D011493:Protein Kinase C; D017923:Sodium-Hydrogen Exchangers; D019311:Staurosporine; C039614:ethylisopropylamiloride