Chen Lihong, Yang Baichun, McNulty Judi A, Clifton Lisa G, Binz Jane G, Grimes Angela M, Strum Jay C, Harrington W Wallace, Chen Zibin, Balon Thomas W, Stimpson Stephen A, Brown Kathleen K
Department of Molecular Pharmacology, GlaxoSmithKline, Inc., Five Moore Drive, Research Triangle Park, NC 27709, USA.
J Pharmacol Exp Ther. 2005 Feb;312(2):718-25. doi: 10.1124/jpet.104.074088. Epub 2004 Oct 8.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have been shown to have significant therapeutic benefits such as desirable glycemic control in type 2 diabetic patients; however, these agents may cause fluid retention in susceptible individuals. Since PPARgamma is expressed selectively in distal nephron epithelium, we studied the mechanism of PPARgamma agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPARgamma agonist. GI262570 (20 mg/kg/day) induced a plasma volume expansion. The plasma volume expansion was accompanied by a small but significant decrease in plasma potassium concentration. Small but significant increases in plasma sodium and chloride concentrations were also observed. These changes in serum electrolytes suggested an activation of the renal mineralocorticoid response system; however, GI262570-treated rats had lower plasma levels of aldosterone compared with vehicle-treated controls. mRNA levels for a group of genes involved in distal nephron sodium and water absorption are changed in the kidney medulla with GI262570 treatment. In addition, due to a possible rebound effect on epithelial sodium channel (ENaC) activity, a low dose of amiloride did not prevent GI262570-induced fluid retention. On the contrary, the rebound effect after amiloride treatment potentiated GI262570-induced plasma volume expansion. This is at least partially due to a synergistic effect of GI262570 and the rebound from amiloride treatment on ENaCalpha expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,K-ATPase system. This may be an important mechanism for PPARgamma agonist-induced fluid retention.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂已被证明具有显著的治疗益处，如在2型糖尿病患者中实现理想的血糖控制；然而，这些药物可能会导致易感个体出现液体潴留。由于PPARγ在远端肾单位上皮细胞中选择性表达，我们使用接受溶剂或强效PPARγ激动剂GI262570（法格列扎）治疗的雄性Sprague-Dawley大鼠，研究了PPARγ激动剂诱导液体潴留的机制。GI262570（20毫克/千克/天）可诱导血浆容量扩张。血浆容量扩张伴随着血浆钾浓度的小幅但显著下降。还观察到血浆钠和氯浓度有小幅但显著的升高。血清电解质的这些变化提示肾盐皮质激素反应系统被激活；然而，与接受溶剂治疗的对照组相比，接受GI262570治疗的大鼠血浆醛固酮水平较低。GI262570治疗后，肾髓质中一组参与远端肾单位钠和水重吸收的基因的mRNA水平发生了变化。此外，由于对上皮钠通道（ENaC）活性可能存在的反弹效应，低剂量的阿米洛利并不能预防GI262570诱导的液体潴留。相反，阿米洛利治疗后的反弹效应增强了GI262570诱导的血浆容量扩张。这至少部分是由于GI262570与阿米洛利治疗对ENaCalpha表达的反弹效应之间的协同作用。总之，我们目前的数据表明，GI262570可通过刺激ENaC和钠钾ATP酶系统增加远端肾单位对水和钠的重吸收。这可能是PPARγ激动剂诱导液体潴留的重要机制。
