Renoprotective and haemodynamic effects of adiponectin and peroxisome proliferator-activated receptor agonist, pioglitazone, in renal vasculature of diabetic Spontaneously hypertensive rats

Abstract

Pioglitazone, a therapeutic drug for diabetes, possesses full PPAR-γ agonist activity and increase circulating adiponectin plasma concentration. Plasma adiponectin concentration decreases in hypertensive patients with renal dysfunctions. Present study investigated the reno-protective, altered excretory functions and renal haemodynamic responses to adrenergic agonists and ANG II following separate and combined therapy with pioglitazone in diabetic model of hypertensive rats. Pioglitazone was given orally [10mg/kg/day] for 28 days and adiponectin intraperitoneally [2.5μg/kg/day] for last 7 days. Groups of SHR received either pioglitazone or adiponectin in combination. A group of Wistar Kyoto rats [WKY] served as normotensive controls, whereas streptozotocin administered SHRs served as diabetic hypertensive rats. Metabolic data and plasma samples were taken on day 0, 8, 21 and 28. In acute studies, the renal vasoconstrictor actions of Angiotensin II [ANGII], noradrenaline [NA], phenylephrine [PE] and methoxamine [ME] were determined. Diabetic SHRs control had a higher basal mean arterial blood pressure than the WKY, lower RCBP and plasma adiponectin, higher creatinine clearance and urinary sodium excretion compared to WKY [all P<0.05] which were normalized by the individual drug treatments and to greater degree following combined treatment. Responses to intra-renal administration of NA, PE, ME and ANGII were larger in diabetic SHR than WKY and SHRs [P<0.05]. Adiponectin significantly blunted responses to NA, PE, ME and ANG II in diabetic treated SHRs by 40%, whereas the pioglitazone combined therapy with adiponectin further attenuated the responses to adrenergic agonists by 65%. [all P <0.05]. These findings suggest that adiponectin possesses renoprotective effects and improves renal haemodynamics through adiponectin receptors and PPAR-γ in diabetic SHRs, suggesting that synergism exists between adiponectin and pioglitazone. A cross-talk relationship also supposed to exists between adiponectin receptors, PPAR-γ and alpha adrenoceptors in renal vasculature of diabetic SHRs.

Fig 1. Baseline renal cortical blood perfusion of WKY, SHR, SHR diabetic control and SHR diabetic treated rats.

The values are presented as mean±S.E.M. (n = 6) in each group and were analyzed by one-way ANOVA followed by Bonferroni post hoc test. Values with (P<0.05) were considered statistically significant.

Fig 2. Adiponectin plasma concentration of WKY, SHR, SHR diabetic control and SHR diabetic treated rats, expressed as μg/ml values.

The values are presented as mean±S.E.M. (n = 6) in each group and were analyzed by one-way ANOVA followed by Bonferroni post hoc test. Values with (P<0.05) were considered statistically significant.

Fig 3. Dose–response curve of the renal vasoconstrictor responses (RCBP % drop) to graded doses of NA in WKY, SHR, SHR diabetic control and SHR diabetic treated rats.

The values are presented as mean±S.E.M. (n = 6) in each group and were analyzed by two-way ANOVA followed by Bonferroni post hoc test. Values with (P<0.05) were considered statistically significant.

Fig 4. Dose–response curve of the renal vasoconstrictor responses (RCBP % drop) to graded doses of PE in WKY, SHR, SHR diabetic control and SHR diabetic treated rats.

The values are presented as mean±S.E.M. (n = 6) in each group and were analyzed by two-way ANOVA followed by Bonferroni post hoc test. Values with (P<0.05) were considered statistically significant.

Fig 5. Dose–response curve of the renal vasoconstrictor responses (RCBP % drop) to graded doses of ME in WKY, SHR, SHR diabetic control and SHR diabetic treated rats.

The values are presented as mean±S.E.M. (n = 6) in each group and were analyzed by two-way ANOVA followed by Bonferroni post hoc test. Values with (P<0.05) were considered statistically significant.

Fig 6. Dose–response curve of the renal vasoconstrictor responses (RCBP % drop) to graded doses of ANG II in WKY, SHR, SHR diabetic control and SHR diabetic treated rats.

The values are presented as mean±S.E.M. (n = 6) in each group and were analyzed by two-way ANOVA followed by Bonferroni post hoc test. Values with (P<0.05) were considered statistically significant.