Angiotensin II Receptor and Postreceptor Events in Adrenal Glomerulosa Cells from Streptozotocin-Induced Diabetic Rats with Hypoaldosteronism Division of Endocrinology

Abstract

Streptozotocin-induced chronic diabetic rats develop hyporeninemic hypoaldosteronism. The hypoaldosteronism is associated with selective unresponsiveness of aldosterone to angiotensin II (AII) and an atrophy of the zona glomerulosa. To assess the nature of the adrenal unresponsiveness to AII, we examined the [125I]monoiodoAII binding and the responses of pregnenolone formation and aldosterone production to AII using adrenal glomerulosa cells from diabetic rats 6 weeks after an injection of streptozotocin. Comparisons were made using the cells from control rats treated with vehicle. Diabetic rats had low levels of plasma renin activity, plasma 18-hydroxycorticosterone, and plasma aldosterone, and normal levels of plasma corticosterone and plasma potassium. The zona glomerulosa width was narrower in diabetic than in control rats. Scatchard analysis of the AII binding data demonstrated that the number and affinity of the receptors were similar in the cells from control and diabetic rats. When corrected to an uniform number of cells per group, baseline levels of pregnenolone formation and aldosterone production were similar in the cells from control and diabetic rats. However, cells from diabetic rats had a less sensitive and lower response of both pregnenolone formation and aldosterone production to AII. In contrast, the effect of ACTH on pregnenolone formation and aldosterone production was similar in the cells from control and diabetic rats. These results indicate that the main defect responsible for the hypoaldosteronism may be located on some step(s) mediating between AII receptors and conversion of cholesterol to pregnenolone, presumably on the calcium messenger system, with a disturbance downstream from AII binding.

Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus: effects of RAAS stimulation

“…reported lower baseline aldosterone levels in a mixed group of diabetic patients with or without diabetic complications than in healthy subjects, with similar relative increases to AngII infusion [11]. In experimental diabetes mellitus a decreased zona glomerulosa width in association with a decreased sensitivity of glomerulosa cells to AngII has been reported [14,15]. In these studies [14,15], the effects of ACTH on aldosterone production were unaltered, suggesting that the main defect responsible for the hypoaldosteronism may be located in the pathways between AngII receptor binding and receptor activation leading to conversion of cholesterol to pregnenolone.…”

“…In experimental diabetes mellitus a decreased zona glomerulosa width in association with a decreased sensitivity of glomerulosa cells to AngII has been reported [14,15]. In these studies [14,15], the effects of ACTH on aldosterone production were unaltered, suggesting that the main defect responsible for the hypoaldosteronism may be located in the pathways between AngII receptor binding and receptor activation leading to conversion of cholesterol to pregnenolone. If this can be extrapolated to man, this may account for either the relative hypoaldosteronism or the decreased adrenal sensitivity to AngI in the presently studied diabetic patients.…”

“…reported absent plasma aldosterone responses despite normal PRA responsiveness to postural changes [9]. Animal studies demonstrated that hypoaldosteronism in diabetes might be related to an impaired responsiveness to AngII [14,15].…”

Potassium Metabolism in Chronic Kidney Disease

“…50 In diabetic animals the impaired response of the zona glomerulosa cells to angiotensin II is caused by a post-receptor defect and is specific to angiotensin II since the aldosterone secretory response to ACTH is not diminished. 51 In patients with normal renal function hypoaldosteronism alone may not be sufficient to cause marked hyperkalemia, since any rise in S[K + ] will have a direct effect to enhance distal tubular K + secretion. This direct effect is diminished in the setting of CKD, suggesting hypoaldosteronism and decreased renal function have synergistic effects in impairing renal tubular K + secretion.…”