Renal angiotensin II AT₂receptors promote natriuresis in streptozotocin-induced diabetic rats

Abstract

Angiotensin II AT 2 receptors have been implicated to play a role in the regulation of renal/cardiovascular functions under pathological conditions. The present study is designed to investigate the function of the AT 2 receptors on renal sodium excretion and AT2 receptor expression in the cortical membranes of streptozotocin (STZ)-induced diabetic rats. The STZ treatment led to a significant weight loss, hyperglycemia, and decrease in plasma insulin levels compared with control rats. STZinduced diabetic rats had significantly elevated basal urine flow, urinary sodium excretion rate (U NaV), urinary fractional sodium excretion, and urinary cGMP compared with control rats. Infusion of PD-123319, an AT 2 receptor antagonist, caused a significant decrease in UNaV (mol/ min) in STZ-induced diabetic rats (1 Ϯ 0.09 vs. 0.45 Ϯ 0.1) but not in control rats (0.35 Ϯ 0.05 vs. 0.4 Ϯ 0.07). The decrease in U NaV was associated with a significant decrease in urinary cGMP levels (pmol/min) in STZ-induced diabetic rats (21 Ϯ 2 vs. 10 Ϯ 0.8) but not in control rats (11.75 Ϯ 3 vs. 12.6 Ϯ 2). The infusion of PD-123319 did not alter glomerular filtration rate (STZ: 0.3 Ϯ 0.02 vs. 0.25 Ϯ 0.03; control: 1.4 Ϯ 0.05 vs. 1.5 Ϯ 0.09 ml/min) or mean arterial pressure (STZ: 82 Ϯ 3 vs. 79 Ϯ 3.5; control: 90 Ϯ 4 vs. 89 Ϯ 4 mmHg), suggesting a tubular effect of the drug. Western blot analysis using an AT 2 receptor antibody revealed a significantly enhanced expression of the AT 2 receptor protein (ϳ45 kDa) in brush-border (ϳ50-fold) and basolateral membranes (ϳ80-fold) of STZ-induced diabetic compared with control rats. In conclusion, our data suggest that the tubular AT 2 receptors in diabetic rats are profoundly enhanced and possibly via a cGMP pathway promote sodium excretion in this model of diabetes. kidney; hypertension OF THE ANGIOTENSIN II receptors, AT 1 receptors are predominantly expressed in adult tissues and perform most of the known ANG II-elicited functions such as vasoconstriction, hypertrophy, and sodium/fluid retention (26). AT 2 receptor expression in adult tissues is relatively low; however, AT 2 receptors are implicated in the cellular and physiological functions that are opposite to the functions mediated by the AT 1 receptors (10,18,19). The activation of AT 2 receptors has been shown to promote cell differentiation and apoptosis (18,26). The AT 2 receptors are also implicated in blood pressure regulation via vasodilatation and possibly affecting fluid/sodium homeostasis (6,12,15).There is evidence that the expression and function of the AT 2 receptors become relevant under pathophysiological conditions (16, 18), such as diabetes. Diabetic patients and animal models exhibit altered sodium/fluid metabolism associated with changes in the renin-angiotensin system (RAS) (1, 27). Because evidence suggests that some of the diabetic animal models may not have altered production of ANG II (8, 12, 21), the altered expression and function of the ANG II receptors may be the site of regulation that affects sodium metabolism in diabe...

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

“…Confirming the reported loss of balance in the levels of AT 1 and AT 2 receptor expression in early diabetes [2,4,5,12,14,17,21], STZ treatments in the present study were paralleled by quantitative and qualitative alterations in the pattern of AT 2 receptor expression in both the adrenal gland and the kidney. 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.…”

“…Along with the reported efficacy of garlic treatments in reducing diabetes-induced AT 1 receptor up-regulation [37], the capacity of garlic in modulating diabetes-induced AT 2 receptor downregulation may imply not only reversing the detrimental consequences of excessive AT 1 receptor signaling, which is pivotal in the dysregulation of adrenal secretions and alterations in renal hemodynamic and tubular functions, but also restoring the recuperative processes mediated by AT 2 receptors in both organs. This notion may be supported by the documented AT 2 -mediated activities in inhibiting aldosterone hypersecretion and regulating catecholamine levels in the adrenal gland [1,[7][8][9]49], inhibiting the sodium pump [53] and Na + -, K + -ATPase activity [20][21][22] in renal proximal tubules thereby promoting natriuresis/diuresis and hypotension, and inhibiting vasoconstriction and cell hypertrophy [7][8][9]18,19] thereby interfering with excessive renal glomerular and tubular remodeling. In this regard, our observations may lend support to the documented efficacy of garlic treatments in ameliorating diabetic complications in STZtreated rats [28][29][30][31][32][33][34][35][36] and further suggest that garlic may alleviate diabetic-induced hypertension and nephropathy by restoring the diabetic-induced loss of balance in AT 1 /AT 2 receptor expression in key target organs.…”

“…Nonetheless, neither the precise mechanisms that underlie the anti-diabetic potentials of garlic nor the nature of the key receptor system(s) targeted, are fully understood. 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].…”

“…Interestingly, early diabetes exerts an opposite influence on AT 2 receptor and significantly decreases its expression in glomeruli and tubular segments of the kidney [17]. The down-regulation of intrarenal AT 2 receptor expression implies the subsequent decrease in AT 2 -mediated mechanisms that may oppose the detrimental effects of AT 1 receptor signaling, including inhibition of cell growth [18,19] as well as NO/cGMP-dependent vasodilatation and inhibition of renal sodium transporters [20][21][22]. This could result in an amplification of AT 1 -mediated effects on vasoconstriction, glomerulosclerosis or cell hypertrophy, and thus contribute further to progressive injury in diabetic nephropathy [17,23].…”

Angiotensin II Type 2 Receptor Agonist Directly Inhibits Proximal Tubule Sodium Pump Activity in Obese But Not in Lean Zucker Rats

“…33 Although D 1 receptor agonist was reported recently to promote AT 2 receptor translocation to the membrane and thereby enhance the AT 2 receptor function to promote natriuresis, 34 it is unlikely that defective D 1 receptor 18 contributed to the enhanced AT 2 receptor function as a compensatory mechanism in obese Zucker rats. 18 Similarly, an upregulation of the renal AT 2 receptor function on tubular sodium metabolism was found in streptozotocin-induced diabetic rats, 35 where dopamine D 1 receptors also are shown to be defective. 36 In addition to the defective dopamine D 1 receptor, we 3,11 and others 23 have reported enhanced Ang II function on tubular sodium transport and hyperantinatriuretic activity in obese compared with lean Zucker rats.…”