School of Pharmaceutical Sciences, University Sains Malaysia, Penang, Malaysia.
Faculty of Pharmacy, MAHSA University, Selangor, Malaysia.
PLoS One. 2020 Nov 10;15(11):e0229803. doi: 10.1371/journal.pone.0229803. eCollection 2020.
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.
吡格列酮是一种治疗糖尿病的药物，具有完全的 PPAR-γ 激动剂活性，并增加循环脂联素血浆浓度。高血压伴有肾功能障碍的患者血浆脂联素浓度降低。本研究探讨了在糖尿病高血压大鼠模型中，分别和联合应用吡格列酮治疗后，对肾上腺素能激动剂和 ANG II 的肾保护、改变的排泄功能和肾血流动力学反应。吡格列酮口服给予 [10mg/kg/天]，共 28 天；脂联素腹腔内给予 [2.5μg/kg/天]，共 7 天。SHR 组分别接受吡格列酮或脂联素治疗。一组 Wistar Kyoto 大鼠 [WKY] 作为正常血压对照，而给予链脲佐菌素的 SHR 作为糖尿病高血压大鼠。在第 0、8、21 和 28 天采集代谢数据和血浆样本。在急性研究中，测定了血管紧张素 II [ANGII]、去甲肾上腺素 [NA]、苯肾上腺素 [PE] 和甲氧基胺 [ME] 的肾血管收缩作用。与 WKY 相比，糖尿病 SHR 对照的基础平均动脉血压更高，肾皮质血压和血浆脂联素更低，肌酐清除率和尿钠排泄量更高[所有 P<0.05]，这些参数在单独药物治疗后得到了纠正，联合治疗后得到了更大程度的纠正。与 WKY 和 SHR 相比，糖尿病 SHR 对肾内给予的 NA、PE、ME 和 ANGII 的反应更大[P<0.05]。脂联素显著减弱了糖尿病治疗 SHR 对 NA、PE、ME 和 ANG II 的反应，减少了 40%，而脂联素与吡格列酮联合治疗进一步减弱了肾上腺素能激动剂的反应，减少了 65%[所有 P<0.05]。这些发现表明，脂联素通过脂联素受体和 PPAR-γ 发挥肾保护作用，并改善糖尿病 SHR 的肾血流动力学，表明脂联素和吡格列酮之间存在协同作用。在糖尿病 SHR 的肾血管中，还存在脂联素受体、PPAR-γ 和α肾上腺素能受体之间的交叉对话关系。
