Antihypertensive and vasculo- and renoprotective effects of pioglitazone in genetically obese diabetic rats

Abstract

Although an improvement of insulin sensitivity has been shown to be a new therapeutic approach for treating diabetes mellitus, details of effects of this treatment on the cardiovascular system and possible renal complications remain unknown. In the present study, we investigated the effects of a thiazolidine derivative, pioglitazone, and examined the insulin-sensitizing action on blood pressure, nephropathy, and vascular changes in genetically obese diabetic Wistar fatty (WF) rats. Pioglitazone (3 mg.kg-1.day-1) was orally administered for 13 wk starting at the age of 5 wk, and the results were compared with those of vehicle-treated WF rats. At the age of 18 wk, vehicle-treated WF rats were associated with mild hypertension, nephropathy with proteinuria histological glomerular injury, and renal arteriolosclerosis in addition to hyperglycemia, hyperinsulinemia, and hyperlipidemia. Treatment with pioglitazone significantly improved glucose and lipid metabolism. In addition, it lowered blood pressure, decreased proteinuria, and prevented glomerular injury, renal arteriolosclerosis, and aortic medial wall thickening, whereas body weight, food intake, sodium balance, and urinary norepinephrine excretion were significantly increased. These results suggest that the insulin-sensitizing agent pioglitazone is effective in correcting not only glucose and lipid metabolism but also cardiovascular and renal complications in non-insulin-dependent diabetes mellitus.

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

“…The latter were in the lower micromolar range (10-15 μM), which is comparable to levels measured in volunteers after oral ingestion of 30 mg pioglitazone (3 μM; [44]). At those concentrations, pioglitazone does increase extracellular fluid volume, as previously shown for PPARγ agonists [18,22,49].…”

“…The use of the PPARγ agonists has, however, been impeded by their volume retaining properties [18,22,49]. In patients with congestive heart failure (CHF), treatment with PPARγ agonists was associated with decompensation and occurrence of pulmonary edema [35].…”

Evaluation of Blood Pressure in Spontaneously Diabetic Torii-Leprfa Rats

“…. Also, Wistar-fatty rats showed mild hypertension [19]. On the other hand, the Goto-Kakizaki (GK) rat, which is a non-obese type 2 diabetic model, did not show obvious hypertension [5].…”

“…Male Wistar-fatty rats and STZ rats showed decreases of heart rate, and those changes might have been caused by heart dysfunction [16,19]. In a further study, it will be necessary to investigate the heart function of SDT-fa/fa rats.…”

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

“…146 Beyond their hypoglycemic actions, PPARЎ agonists exert a number of beneficial effects in diabetes including improvement in endothelial function, 147,148 reduction in pro-atherogenic inflammatory markers 149 and angiotensin-I and -II, 150 down regulation of AT 1 mRNA and protein in vascular smooth muscle cells, 151,152 decrease in urine endothelin-1 secretion, 153 attenuated lipid accumulation and its related injury in mesangial cells, 154,155 and inhibition of glomerular and tubular cell proliferation 156,157 . Several animal [158][159][160][161][162][163] and human studies 153,[164][165][166][167][168][169][170][171][172][173][174][175] using various TZDs have demonstrated a reduction in proteinuria and BP. Unfortunately; most of these studies were of short duration averaging 1-9 months in the animal studies 158-163 and 3-12 months in human studies.…”