Increased Renal Angiotensin II AT<sub>1</sub>Receptor Function in Obese Zucker Rat

Becker, Misti; Umrani, Dhananjay N.; Lokhandwala, Mustafa F.; Hussain, Tahir

doi:10.1081/ceh-120017739

Cited by 39 publications

(38 citation statements)

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“…Even before the development of diabetes, ZDF rats have increased pressor responsiveness to Ang II (33). In the kidney, this may be related to increased AT 1 receptor abundance and function (34). Consistent with this finding, expression of AT 1 receptor protein was increased more than threefold in the islets of ZDF rats, correlating with fibrosis and ␤-cell loss.…”

Section: Discussionsupporting

confidence: 74%

Improved Islet Morphology after Blockade of the Renin- Angiotensin System in the ZDF Rat

et al. 2004

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The renin-angiotensin system (RAS) has an important role in the endocrine pancreas. Although angiotensin II has significant effects on cell proliferation and apoptosis, the contribution of the RAS to changes in islet structure and function associated with type 2 diabetes is yet to be defined. This study examined the specific effects of RAS blockade on islet structure and function in diabetes. Thirty-six male Zucker diabetic fatty (ZDF) rats, 10 weeks of age, were randomized to receive the angiotensin-converting enzyme inhibitor perindopril (8 mg/l in drinking water; n ‫؍‬ 12), irbesartan (15 mg/kg via gavage; n ‫؍‬ 12), or no treatment (n ‫؍‬ 12) for 10 weeks. Results were compared with lean littermates (ZL) (n ‫؍‬ 12) studied concurrently. ZDF rats had increased intraislet expression of components of the RAS correlating with increased intraislet fibrosis, apoptosis, and oxidative stress. Disordered islet architecture, seen in ZDF rats, was attenuated after treatment with perindopril or irbesartan. Islet fibrogenesis was also diminished, as measured by picrosirius staining and expression of collagens I and IV. Gene expression of transforming growth factor-␤1 was increased in the ZDF pancreas (ZL, 1.0 ؎ 0.1; ZDF, 2.0 ؎ 0.3; P < 0.05) and reduced after blockade of the RAS (ZDF ؉ P, 1.3 ؎ 0.2; ZDF ؉ I, 1.5 ؎ 0.1; vs. ZDF, both P < 0.05). Improvements in structural parameters were also associated with functional improvements in first-phase insulin secretion. These findings provide a possible mechanism for the reduced incidence of new-onset diabetes that has been observed in clinical trials of RAS blockade. Diabetes 53: 989 -997, 2004

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Section: Discussionsupporting

confidence: 74%

Improved Islet Morphology after Blockade of the Renin- Angiotensin System in the ZDF Rat

et al. 2004

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“…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. Compared with the AT 2 receptors, in general, the AT 1 receptors are the predominant receptor subtype; therefore, the net effect of Ang II is believed to be mediated via the activation of the AT 1 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that, on one hand, the renal dopamine D 1 receptor, a natriuretic hormone receptor, function is defective, 18 and on the other hand, Ang II function with an antinatriuretic effect is hyperactive in obese Zucker rats. 11 However, we reported recently that AT 2 receptors are upregulated in the cortical membranes of obese Zucker rats, and on selective activation, the AT 2 receptors (4 lean rats and 6 obese rats); *PϽ0.05 vs basal within the same group (ANOVA followed by Newman-Keuls multiple comparison test). #PϽ0.05 vs lean (Student t test) (B) Effect of CGP42112 (10 nmol/L) on nitrite/nitrate formation in the proximal tubular suspension isolated from lean and obese Zucker rats, in the absence and presence of PD123319 (1 mol/L), and L-NAME (100 mol/L).…”

Section: Discussionmentioning

confidence: 99%

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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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“…In experimental models of diabetes, several abnormalities of blood pressure regulation and sodium handling have been reported (1)(2)(3)(4). It is likely that an overactivity of antinatriuretic factors and a dysfunction in natriuretic factors contribute to sodium retention (5)(6)(7). Dopamine promotes sodium excretion via activation of renal D1 receptors (8).…”

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confidence: 99%

Tempol Reduces Oxidative Stress, Improves Insulin Sensitivity, Decreases Renal Dopamine D1 Receptor Hyperphosphorylation, and Restores D1 Receptor–G-Protein Coupling and Function in Obese Zucker Rats

et al. 2005

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Oxidative stress plays a pathogenic role in hypertension, particularly the one associated with diabetes and obesity. Here, we test the hypothesis that renal dopamine D1 receptor dysfunction in obese Zucker rats is caused by oxidative stress. One group each from lean and obese Zucker rats received tempol, a superoxide dismutase mimetic in drinking water for 2 weeks. Obese animals were hypertensive, hyperglycemic, and hyperinsulinemic, exhibited renal oxidative stress, and increased protein kinase C activity. Also, there was hyperphosphorylation of D1 receptor, defective receptor-G-protein coupling, blunted dopamine-induced Na ؉ -K ؉ -ATPase inhibition, and diminished natriuretic response to D1 receptor agonist, SKF-38393. However, obese animals had elevated levels of plasma nitric oxide and urinary cGMP. In addition, L-N-nitroarginine and sodium nitroprusside showed similar effect on blood pressure in lean and obese rats. In obese animals, tempol reduced blood pressure, blood glucose, insulin, renal oxidative stress, and protein kinase C activity. Tempol also decreased D1 receptor phosphorylation and restored receptor G-protein coupling. Dopamine inhibited Na ؉ -K ؉ -ATPase activity, and SKF-38393 elicited a natriuretic response in tempol-treated obese rats. Thus in obese Zucker rats, tempol ameliorates oxidative stress and improves insulin sensitivity. Consequently, hyperphosphorylation of D1 receptor is reduced, leading to restoration of receptor-G-protein coupling and the natriuretic response to SKF-38393. Diabetes 54: 2219 -2226, 2005

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Increased Renal Angiotensin II AT₁Receptor Function in Obese Zucker Rat

Cited by 39 publications

References 39 publications

Improved Islet Morphology after Blockade of the Renin- Angiotensin System in the ZDF Rat

Improved Islet Morphology after Blockade of the Renin- Angiotensin System in the ZDF Rat

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

Tempol Reduces Oxidative Stress, Improves Insulin Sensitivity, Decreases Renal Dopamine D1 Receptor Hyperphosphorylation, and Restores D1 Receptor–G-Protein Coupling and Function in Obese Zucker Rats

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Increased Renal Angiotensin II AT1Receptor Function in Obese Zucker Rat

Cited by 39 publications

References 39 publications

Improved Islet Morphology after Blockade of the Renin- Angiotensin System in the ZDF Rat

Improved Islet Morphology after Blockade of the Renin- Angiotensin System in the ZDF Rat

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

Tempol Reduces Oxidative Stress, Improves Insulin Sensitivity, Decreases Renal Dopamine D1 Receptor Hyperphosphorylation, and Restores D1 Receptor–G-Protein Coupling and Function in Obese Zucker Rats

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Increased Renal Angiotensin II AT₁Receptor Function in Obese Zucker Rat