Garlic (Allium sativum) down-regulates the expression of angiotensin II AT1 receptor in adrenal and renal tissues of streptozotocin-induced diabetic rats

Abstract

The up-regulation of angiotensin II AT1 receptors has been implicated as a major mediator in the development of hypertension and progressive nephropathy in experimental diabetes. In spite of the documented potential of garlic treatments in ameliorating diabetic complications, the possible involvement of the angiotensin II AT1 receptor, as a central target for the anti-diabetic potential of garlic, has not been explored. Three groups of rats were studied after 8 weeks following diabetes induction: normal, streptozotocin-induced diabetic (control diabetic), and garlic-treated diabetic rats. A polyclonal antibody of proven specificity to the AT1 receptor, as verified by western blotting, indicated in immunohistochemical assays that AT1 receptor labeling was significantly increased in adrenal and renal tissues of control diabetic rats compared to the normal group. The increased AT1 receptor labeling involved all cortical zones and medullary chromaffin cells of the adrenal gland. Except for glomerulii, increased AT1 receptor labeling was also evident in proximal convoluted tubules in the renal cortex, and all tubular segments and interstitial cells outlining the vasa recta bundles in the inner stripe of the outer renal medulla. Compared with control diabetic rats, the labeling of the AT1 receptor in the garlic-treated diabetic group was significantly reduced throughout adrenal and renal regions to levels comparable to those observed in normal rats. The capacity of garlic to modulate diabetes-induced AT1 receptor up-regulation may be implicated in reversing the detrimental consequences of excessive Ang II signaling, manifested by the development of hypertension and nephropathy.

Garlic (<i>allium sativum</i>) modulates the expression of angiotensin II AT<sub>2</sub> receptor in adrenal and renal tissues of streptozotocin-induced diabetic rats

“…In the kidney, the present study also revealed that STZ treatments were associated with a significant decrease in AT 2 receptor expression throughout all nephronal segments including glomeruli and proximal and distal convoluted tubules in the cortex, collecting tubules and ducts and ascending Henle's loop segments in the inner stripe of the outer medulla, as well as inner medullary collecting ducts. The observed decrease in total intrarenal expression of AT 2 receptors is in direct accordance with previous observations in the same model of experimental diabetes [17], and contrasts the documented effects of STZ treatments in upregulating intrarenal expression of AT 1 receptors [1,2,4,11,12,24,26,37]. Thus, in early diabetes, the expected decline in AT 2 -mediated mechanisms may potentiate the pathological augmentation of intrarenal AT 1 -mediated activities promoting sodium retention and hypertension, glomerulosclerosis and proteinuria, tubulo-interstitial cell hypertrophy and hyperplasia associated with stimulation of extracellular matrix production, which are the hallmark of diabetic nephropathy [2,[12][13][14][15][16].…”

“…The significant reduction of AT 2 receptor expression in adrenomedullary chromaffin cells may be also implicated in a possible loss of the synergistic AT 1 /AT 2 receptor cross-talk suggested to regulate basal and stress-induced tyrosine hydroxylase transcription rates [49], and thereby leading to dysregulation of adrenomedullary catecholamine secretions. Interestingly, the up-regulatory shift in AT 2 receptor expression in the zona fasiculata/reticularis, which was also observed earlier for AT 1 receptor expression [37], has been consistently observed with either receptor type under various abnormal physiological and pathophysiological conditions including dietary sodium restriction, sodium loading, stimulated levels of aldosterone or Ang II, and water deprivation [47,[50][51][52]. Although the exact functional significance of AT 1 /AT 2 receptor perturbations in these zones is still to be elucidated, their altered expression may represent a signifi-cant adaptive factor in adrenal tissue remodeling under various pathological conditions, including early diabetes.…”

“…Compared to normal rats, the highest adrenocortical AT 2 receptor expression was significantly shifted from the zona glomerulosa to the zona fasciculate/reticularis, and was significantly reduced in adrenomedullary chromaffin cells of STZtreated, control diabetic rats. In this rat group, the reduction of AT 2 receptor expression in the zona glomerulosa was in direct contrast to the increase in AT 1 receptor expression observed in this zone in an earlier report [37] and may imply a decrease in AT 2 -mediated inhibition of cell growth [18,19] and the amplification of AT 1 -mediated effects on cell hypertrophy and aldosterone synthesis and release [2][3][4][5], leading to electrolyte imbalance and the development of hypertension. The significant reduction of AT 2 receptor expression in adrenomedullary chromaffin cells may be also implicated in a possible loss of the synergistic AT 1 /AT 2 receptor cross-talk suggested to regulate basal and stress-induced tyrosine hydroxylase transcription rates [49], and thereby leading to dysregulation of adrenomedullary catecholamine secretions.…”

“…Nonetheless, the potential of garlic in targeting the level of expression of Ang II receptors is, as yet, not fully explored. In a recent study, we reported on the efficacy of an aqueous extract of raw garlic in modulating the upregulated expression of Ang II AT 1 receptors in the adrenal and renal tissues in early diabetes [37]. In the present study, immunohistochemical evidence is presented for the capacity of garlic treatments to modulate the down-regulated expression of Ang II AT 2 receptors in adrenal and renal tissues of streptozotocin-induced diabetic rats.…”

“…In hypertensive diabetic rats, altered gene and protein expression of the Ang II AT 1 and AT 2 receptor types and the loss of balance between their antagonistic activities, in renal and other tissues, have been directly implicated in the development of early changes associated with diabetic nephropathy [2,4,5,12,14,17,21]. In a recent report, the remarkable capacity of garlic treatments to modulate the upregulated expression of AT 1 receptors, associated with hypersecretion of aldosterone and the impairment of renal vascular and tubular functions in early diabetes, has been demonstrated [37]. The present study was designed to investigate the level of expression of the AT 2 receptor in the adrenal and renal tissues of normal, control diabetic and garlic-treated diabetic rats.…”