Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity.
The objective of this study was to determine the effect of pioglitazone on blood pressure (BP) and oxidative balance in obese, hypertensive, Sprague-Dawley rats and to identify some of the molecular mechanisms involved. After 12 weeks of a moderately high-fat diet, rats diverged into obesity-prone (OP) and obesity-resistant (OR) groups (n=6 per group). At the end of the diet, peroxisome proliferator activated receptor-gamma (PPARgamma) mRNA expression and activity in the renal cortex and medulla of OP rats were significantly lower compared with that in OR rats. Pioglitazone treatment increased PPARgamma expression and activity in OP rats, suggesting a possible direct ligand-related effect of pioglitazone. As opposed to the untreated OP group, which showed moderate hypertension (systolic BP=159+/-5.3 mm Hg) after 12 weeks, pioglitazone-treated rats were normotensive (systolic BP=123.9+/-2.7 mm Hg). Insulin production was reduced by 2-fold in the OP group treated with pioglitazone. Urinary isoprostanes and renal lipid peroxides were also reduced in OP rats treated with pioglitazone compared with untreated counterparts. Also, expression of p47phox and gp91phox, both increased in OP versus OR rats, was reduced in the former by pioglitazone treatment. In addition, pioglitazone treatment increased nitrate/nitrite excretion and expression of renal endothelial and neuronal nitric oxide synthase. Collectively, the results show that pioglitazone treatment prevented hypertension and renal oxidative stress both by reducing free-radical production and by increasing nitric oxide production/availability.
Dobrian
Anca D
AD
Department of Physiological Sciences, Eastern Virginia Medical School, 700W Olney Rd, Norfolk, Va 23507, USA. dobriaad@evms.edu
Schriver
Suzanne D
SD
Khraibi
Ali A
AA
Prewitt
Russell L
RL
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004032:Diet; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000209:etiology; D018384:Oxidative Stress; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012964:Sodium / Q000652:urine; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014157:Transcription Factors / Q000378:metabolism; D014810:Vitamin E / Q000627:therapeutic use
D000959:Antihypertensive Agents; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D014810:Vitamin E; D009569:Nitric Oxide; D012964:Sodium; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D000077205:Pioglitazone