Renal Angiotensin II Type-2 Receptors Are Upregulated and Mediate the Candesartan-Induced Natriuresis/Diuresis in Obese Zucker Rats

Hakam, Amer C.; Hussain, Tahir

doi:10.1161/01.hyp.0000151622.47814.6f

Cited by 73 publications

(125 citation statements)

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“…As a result, altered renal Na ϩ handling in AT 2 -null mice could be the result of AT 1 receptor upregulation and not a specific AT 2 receptor-mediated effect. Hakam and Hussain 19 showed that intravenous infusion of PD, a specific AT 2 receptor antagonist, abolished the CANDinduced natriuresis/diuresis in obese Zucker rats (a genetic model of obesity and hyperinsulinemia) to a greater degree than in lean rats. In their studies, direct stimulation of AT 2 receptors with CGP-42112A produced a more significant natriuresis/diuresis in obese compared with lean rats.…”

Section: Discussionmentioning

confidence: 99%

Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat

et al. 2006

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Abstract-Whereas angiotensin (Ang) II is the major effector peptide of the renin-angiotensin system, its metabolite, des-aspartyl 1 -Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT 1 ) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT 2 ) blocker, on Na ϩ excretion (U Na V) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on U Na V with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na ϩ intake, RI CAND increased U Na V from 0.07Ϯ0.08 to 0.82Ϯ0.17 mol/min (PϽ0.01); this response was abolished by PD. During Na ϩ restriction, CAND increased U Na V from 0.06Ϯ0.02 to 0.1Ϯ0.02 mol/min (PϽ0.05); this response also was blocked by PD. In rats with both kidneys intact, in the absence of CAND, unilateral RI infusion of Ang III did not significantly alter U Na V. However, with systemic CAND infusion, RI Ang III increased U Na V from 0.08Ϯ0.01 mol/min to 0.18Ϯ0.04 mol/min (PϽ0.01) at 3.5 nmol/kg per minute, and U Na V remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter U Na V at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT 1 receptor blockade engenders natriuresis by activation of AT 2 receptors. AT 2 receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT 1 receptor blockade. Key Words: angiotensin Ⅲ sodium Ⅲ natriuresis Ⅲ angiotensin Ⅲ receptors, angiotensin II A ngiotensin (Ang) II, the primary transducer peptide of the renin-Ang system (RAS), acts at 2 major Ang II receptors, type 1 (AT 1 ) and type 2 (AT 2 ). 1 The majority of Ang II actions are believed to occur via the AT 1 receptor, including antinatriuresis. 2 The role of the AT 2 receptor is less clearly understood. 3 Furthermore, whereas Ang II has been considered the major effector peptide of the RAS, its direct metabolite, des-aspartyl 1 -Ang II (Ang III) also has biologic activity. 4 Indeed, some actions originally attributable to Ang II, such as vasopressin release, are mediated at least in part by Ang III. 5 Recent reports suggest that Ang III could be involved in renal physiological processes as well. 6 -8 Studies involving AT 2 receptors and the regulation of sodium (Na ϩ ) excretion have been limited. In vitro studies have demonstrated that the AT 2 receptor may decrease renal proximal tubule bicarbonate reabsorption via phospholipase A 2 and arachidonic acid release. 9 In vivo studies in mice lacking the AT 2 receptor (AT 2 -null), have demonstrated a shift to the right (less sensitive) in the pressure-natriuresis curve. 10 In addition, antinatriuretic and pressor hypersensitivity to Ang II has been documented in AT 2 -null mice. 11 However, th...

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Section: Discussionmentioning

confidence: 99%

Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat

et al. 2006

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“…The AT 1 receptors are ubiquitously expressed and are involved in mediating the Ang II-associated vasoconstriction, cell growth, and sodium retention. 2 The AT 2 receptors are expressed in various tissues 3,4 and are associated with vasodilatation, apoptosis, antiproliferation, and natriuresis 2,3,5 and, therefore, can be considered as functional antagonists to the AT 1 receptors.…”

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confidence: 99%

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confidence: 99%

“…3 Selective activation of the AT 2 receptors by CGP42112 promotes natriuresis/diuresis to a greater degree in obese compared with lean Zucker rats. 3 The obese Zucker rat is a genetic model of insulin resistance that develops mild hypertension. 3,6 It has been shown that the RAS is overactive in obesity 7 and that obesity-associated hypertension is linked to increased sodium reabsorption.…”

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

Hakam

Hussain

2006

Hypertension

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Abstract-We have reported recently that the renal angiotensin II type 2 (AT 2 ) receptors are upregulated and involved in promoting natriuresis/diuresis in obese but not in lean Zucker rats. In the present study, we tested the hypothesis that there is an enhanced AT 2 receptor signaling via NO/cGMP pathway leading to greater inhibition of the Na ϩ , K ϩ -ATPase (NKA) activity in the proximal tubules (PT) of obese rather than lean Zucker rats. The AT 2 agonist CGP42112 (0.1 to 100 nmol/L) inhibited (33% at 100 nmol/L) the NKA activity in the PTs of obese but not in lean Zucker rats. The AT 2 antagonist PD123319 (1 mol/L), not the angiotensin II type 1 antagonist losartan (1 mol/L), significantly diminished the CGP42112-induced inhibition of the NKA activity in obese rats. The AT 2 agonist (10 nmol/L)-induced NKA inhibition was abolished by the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 mol/L), the NO synthase inhibitor N G -nitro-L-arginine methyl ester (100 mol/L), and the protein kinase G inhibitor K1388 (2 mole/L). CGP42112 (10 nmol/L) caused an increase in serine phosphorylation of NKA ␣1-subunit in PT of obese rats. Measurement of cGMP and NO revealed that CGP42112 (0.1 to 100 nmol/L) increased cGMP and NO accumulation in the PTs of obese but not lean rats. The CGP42112-induced stimulation of NO and cGMP was blocked by PD123319 (1 mol/L), N G -nitro-L-arginine methyl ester (100 mol/L), and 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 mol/L) but not by losartan (1 mol/L). The data suggest that the AT 2 receptor activation via stimulation of the NO/cGMP/protein kinase G pathway directly inhibits the tubular NKA activity that provides as a mechanism responsible for the AT 2 receptor-mediated natriuresis in obese but not in lean Zucker rats.

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“…[23][24][25] In the adult kidney, AT 2 receptors are mainly localized in the glomerular mesangial cells 22,26,27 or the adventitia of the preglomerular arcuate and interlobular arteries. 28 AT 2 receptors are upregulated in the adult kidney in response to sodium depletion 27 or kidney damage 29 in obese Zucker rats 30 and spontaneously hypertensive rats (SHRs). 31 In other pathological conditions, such as stroke, an increased AT 2 receptor gene expression in the infarcted cortex was reported.…”

Section: Angiotensin II At 1 and At 2 Receptorsmentioning

confidence: 99%

Blood pressure and renal hemodynamic effects of angiotensin fragments

Yang

Smolders

Dupont³

2011

Hypertens Res

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Renal Angiotensin II Type-2 Receptors Are Upregulated and Mediate the Candesartan-Induced Natriuresis/Diuresis in Obese Zucker Rats

Cited by 73 publications

References 33 publications

Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat

Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat

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

Blood pressure and renal hemodynamic effects of angiotensin fragments

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