Ighodaro Igbe, Eric Omogbai Kelly, Adebayo Oyekan
Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Benin.
Niger J Physiol Sci. 2013 Dec 20;28(2):127-33.
Diminished insulin sensitivity is a characteristic feature of various pathological conditions such as hypertension and activation of peroxisome proliferator activated receptor α (PPARα) has been shown to enhance insulin resistance and reduce capacity for glucose uptake in muscles. The present study was designed to evaluate the interactions of PPARα and GLUT4 in a model of hypertensive renal injury by studying deoxycorticosterone acetate (DOCA)-salt induced hypertension in wild-type (WT) and PPARα knockout (KO) mice. PPARα WT and KO mice were uninephrectomized (UNx) and implanted subcutaneously DOCA and drank 1% sodium chloride/1% potassium chloride with or without a GLUT4 antagonist, indinavir (20 mg/kg/day, s.c) or PPARα ligand, fenofibrate (100 mg/kg/day, orally). DOCA/salt treatment increased urinary sodium excretion and urine volume (p<0.05) in PPARα KO mice compared to WT littermates. Indinavir increased proteinuria (p<0.01) in DOCA/salt-treated PPARα KO mice compared to WT littermates but did not affect heart and kidney weight index in DOCA/salt KO or WT-treated mice. Urinary sodium excretion (UNaV) and urine volume (UV) were increased by indinavir (p<0.01) and fenofibrate (p<0.05) in DOCA/salt-treated PPARα KO mice compared to WT mice. Urinary nitric oxide was greater in both fenofibrate (p<0.05) and indinavir-treated WT mice (p<0.05) compared to KO mice. These data suggest that in hypertensive nephropathy, GLUT4 probably exerts a renoprotective role that was enhanced with the activation of PPARα receptors by a mechanism that may be related to increased nitric oxide production.
胰岛素敏感性降低是多种病理状况（如高血压）的特征性表现，而过氧化物酶体增殖物激活受体α（PPARα）的激活已被证明会增强胰岛素抵抗，并降低肌肉摄取葡萄糖的能力。本研究旨在通过研究野生型（WT）和PPARα基因敲除（KO）小鼠中醋酸脱氧皮质酮（DOCA）-盐诱导的高血压模型，评估PPARα与葡萄糖转运蛋白4（GLUT4）在高血压肾损伤模型中的相互作用。PPARα野生型和基因敲除小鼠进行单侧肾切除（UNx），皮下植入DOCA，并饮用1%氯化钠/1%氯化钾，同时给予或不给予GLUT4拮抗剂茚地那韦（20mg/kg/天，皮下注射）或PPARα配体非诺贝特（100mg/kg/天，口服）。与野生型同窝小鼠相比，DOCA/盐处理使PPARα基因敲除小鼠的尿钠排泄和尿量增加（p<0.05）。与野生型同窝小鼠相比，茚地那韦使DOCA/盐处理的PPARα基因敲除小鼠的蛋白尿增加（p<0.01），但对DOCA/盐基因敲除或野生型处理小鼠的心脏和肾脏重量指数没有影响。与野生型小鼠相比，茚地那韦（p<0.01）和非诺贝特（p<0.05）使DOCA/盐处理的PPARα基因敲除小鼠的尿钠排泄（UNaV）和尿量（UV）增加。与基因敲除小鼠相比，非诺贝特（p<0.05）和茚地那韦处理的野生型小鼠（p<0.05）的尿一氧化氮水平更高。这些数据表明，在高血压肾病中，GLUT4可能发挥肾脏保护作用，并且通过一种可能与一氧化氮生成增加相关的机制，PPARα受体的激活可增强这种作用。
