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

Banday, Anees Ahmad; Marwaha, Aditi; Tallam, Lakshmi S.; Lokhandwala, Mustafa F.

doi:10.2337/diabetes.54.7.2219

Cited by 104 publications

(171 citation statements)

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“…However, endogenous renal dopamine production is normal or even increased in obese humans (46), monkeys (43), and rats (39). Therefore, the dopaminergic defect in the obese male rat has been suggested to be at the receptor or postreceptor level (4,5,7,23,24,40). Our finding of decreased renal expression of D1R in obese male rats provides a potential explanation for the reduced D1-like dopaminergic signaling previously reported in the proximal tubule of these rats (5,31).…”

Section: Discussionsupporting

confidence: 48%

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

Wang

José

et al. 2010

American Journal of Physiology-Renal Physiology

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Ecelbarger CM. Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II. Am J Physiol Renal Physiol 299: F1164-F1170, 2010. First published September 1, 2010 doi:10.1152/ajprenal.00604.2009.-Dopamine produced by renal proximal tubules increases sodium excretion via a decrease in renal sodium reabsorption. Dopamine natriuresis is impaired in obese Zucker rats; however, the mechanism is not fully understood. To test the hypothesis that renal expression of one or more of the subtypes are altered in these rats, we measured whole kidney protein levels by immunoblotting of D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) dopamine receptors in both male and female obese and lean Zucker rats. In obese males on 1% NaCl diet, D1R, D2R, D4R, and D5R were decreased, while D3R was increased, relative to lean rats. Under a 4% NaCl diet, D2R and D3R levels in obese rats were restored to lean levels. 4% NaCl diet reduced D5R in both body types, relative to 1% NaCl diet. Female rats had higher expression of D1R and D3R than did male; however, the sex difference for D1R was markedly blunted in obese rats. In obese rats, dietary candesartan (angiotensin II type 1 receptor blocker) normalized downregulated D1R and D2R, but either decreased (D3R), did not affect (D4R), or further downregulated (D5R) the other subtypes. Candesartan also decreased D4R in lean rats. In summary, reduced renal protein levels of D1R, D2R, D4R, and D5R in obese Zucker rats could induce salt sensitivity and elevate blood pressure. Increased angiotensin II type 1 receptor activity may be mechanistically involved in the decreased expression of D1R and D2R in obese rats. Finally, reduced D1R and D3R in male rats may contribute to sex differences in blood pressure.

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Section: Discussionsupporting

confidence: 48%

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

Wang

José

et al. 2010

American Journal of Physiology-Renal Physiology

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“…Previously it has also been known that SOD mimetics are known to function as either antioxidants or prooxidants depending on the experimental conditions (33). Tempol treatment induced oxidative stress and impaired mitochondrial function in vascular endothelial and smooth muscle cells (34), while treatment with tempol in drinking water reduces oxidative stress in obese Zucker rats (35). The exact mechanism of this prooxidant effect of tempol in our study is not known, but we speculate that increased accumulation of H 2 O 2 may cause oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Lipid Infusion–Induced Skeletal Muscle Insulin Resistance by Cotreatment With Tempol and Glutathione in Mice

et al. 2009

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Abstract. In the present study, we examined whether lipid infusion-induced insulin resistance in skeletal muscle could be reversed by the antioxidants tempol, glutathione (GSH), or tempol with GSH in male C57BL/6J mice via hyperinsulinemic-euglycemic clamp. Lipid infusion increased the mRNA level of mitochondrial type superoxide dismutase (Mn-SOD), glutathione peroxidase 1, tumor necrosis factor-α, and interleukin-6. Lipid infusion decreased GSH and GSH /glutathione disulfide (GSSG) ratio and increased the activities of JNK and p38 in skeletal muscle. Lipid infusion induced insulin resistance in whole body and skeletal muscle. Treatment with the SOD mimetic tempol did not prevent oxidative stress, the inflammatory response, and insulin resistance induced by lipid infusion. Tempol alone increased oxidative stress and aggravated the lipid-induced inflammatory response. GSH at 100 and 200 μmol ⋅ kg −1 ⋅ h −1 did not prevent insulin resistance and the inflammatory response by lipid infusion. On the contrary, GSH at 100 μmol ⋅ kg −1 ⋅ h −1 with tempol prevented insulin resistance in the whole body and skeletal muscle, and it completely reversed oxidative stress and the inflammatory response. These results suggest that lipid infusion-induced insulin resistance in skeletal muscle is produced by oxidative stress and cotreatment with tempol and GSH inhibits lipid-induced insulin resistance.

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“…This notion is supported by the reports that cortical NO synthase activity was lower 28 and sodium nitroprusside, an NO donor that directly activates soluble guanylate cyclase, produced a similar degree of NKA inhibition in obese and lean Zucker rats. 29 To test whether AT 2 receptor-mediated NKA inhibition was a direct effect or whether changes in the sodium entry from apical side were responsible for this inhibition, we performed 2 sets of experiments. In 1 set, gramicidin, which disrupts the sodium gradient between the intracellular and extracellular spaces, did not affect the AT 2 -mediated inhibition of the NKA activity in obese rats.…”

Section: Discussionmentioning

confidence: 99%

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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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

Cited by 104 publications

References 50 publications

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

Inhibition of Lipid Infusion–Induced Skeletal Muscle Insulin Resistance by Cotreatment With Tempol and Glutathione in Mice

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

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