Abstract. Experimental studies demonstrate impaired regulation of the mesangial angiotensin I1 (AII) receptor in diabetes. This could contribute to the disturbance of glomerular blood flow and the development of diabetic nephropathy. The aim of this study was to determine whether a similar receptor abnormality occurs in patients with type I insulin-dependent diabetes mellitus (IDDM) and if so whether this is more prevalent in patients with micro-or macro-albuminuria. The platelet A11 receptor was chosen because of its availability from the circulation and its comparable regulatory properties to tissue-based receptors. The interaction between plasma All and its platelet receptor was examined in 45 patients with TDDM and 36 age-and sex-matched control subjects. Seven patients had clinical nephropathy and two had persistent micro-albuminuria. The duration of diabetes varied from 1 month to 42 years.There was a significant inverse correlation between plasma AIT and the logarithm of receptor number in the control group ( r = -0.555, P<0.001). This relationship was not observed in the diabetic patients irrespective of the duration of disease or the presence of nephropathy. Receptor expression in patients without nephropathy showed no correlation with either duration of disease or the degree of glycaemic control. However, a significant relationship between AT1 receptor number and duration of diabetes was noted in the group with nephropathy (r = 0.723, P < 0.05). Patients without nephropathy had a significantly lower receptor number than control subjects (i.e. 3.9k0.4 and 5.1 kO.7 sites per cell respectively; P=0.02), while comparable values to controls were observed in patients with renal disease (5.7-l 1.2 sites per cell). Plasma renin and A11 levels for both groups ofpatients were comparable to those observed in the control subjects.If these findings are representative of tissue-based A11 receptors, then the loss of ligand/receptor relationship in the presence of higher receptor expression in patients with nephropathy could provide an explana- tion for the glomerular haemodynamic abnormalities observed in human diabetes.
The effects of enalapril and verapamil on glomerular protein content, fractional mesangial area and glomerular basement membrane (GBM) thickness were examined in spontaneously hypertensive rats with streptozotocin-induced diabetes. Two groups of 16 animals received enalapril maleate or verapamil to achieve normal blood pressure while a third untreated group remained hypertensive throughout the 3 month experimental period. Blood glucose levels were maintained at 6-10 mmol/L in each group. Creatinine clearance and 24 h urine protein were measured at second weekly intervals. Glomerular protein and other structural parameters were measured at the end of the experiment. Plasma angiotensin I1 (AII) and glomerular A11 receptors were also quantitated at the end of the experiment. At 3 months, proteinuria was lowest in the enalapril-treated animals while creatinine clearance was lower in the treated groups than controls. Glomerular protein content (pg/glomerulus) was lower in the enalapril-treated group than verapamiltreated (P< 0.01) or untreated rats (P< 0.05). Kidney weight, GBM thickness and fractional mesangial area were also lowest in this group (P< 0.001 compared to other groups). Glomerular A11 receptor number was comparable among groups when expressed as sites/glomerulus. The data suggest that enalapril reduces glomerular protein content independently of blood pressure control and that this effect corresponds with changes in mesangial area and GBM thickness.
1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII-R) relationship in streptozotocin-induced diabetes was investigated as well as the effect of glycaemic control on this relationship. 2. Diabetes was induced in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with streptozotocin 60 mg/kg and blood sugars maintained between 18-21 mmol/L (uncontrolled diabetes) and 4-8 mmol/L (controlled diabetes). Rats were killed on days 1 and 7. Angiotensin II receptor was estimated by saturation analysis and plasma AII by radio-immunoassay. 3. Angiotensin II receptors were significantly higher in non-diabetic SHR than WKY rats (708 +/- 62 and 388 +/- 36 fmol/mg protein, respectively, P = 0.0008). Plasma AII were comparable in both groups (47 +/- 2.7, 38 +/- 3.5 pg/mL, respectively) and a significant inverse relationship between AII/AII-R was observed (WKY P = 0.02 and SHR P = 0.004). 4. On day 7, plasma AII and AII-R levels in diabetic groups were comparable with those of their non-diabetic controls. Diabetic WKY rats maintained an inverse correlation between AII and AII-R (controlled P = 0.04 and uncontrolled P = 0.015), but this did not occur in the SHR. 5. Absence of receptor response to varying ligand concentrations in the diabetic SHR may contribute to the development of nephropathy. Glycaemic control does not appear to reverse this abnormality in the SHR, so that co-existent hypertension may have a more direct influence on renal function.
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