Time course of AQP-2 and ENaC regulation in the kidney in response to PPAR agonists associated with marked edema in rats.
Time course of AQP-2 and ENaC regulation in the kidney in response to PPAR agonists associated with marked edema in rats.
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DOI：
10.1016/j.phrs.2008.03.013
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发表时间：
2008-05
影响因子：
9.3
通讯作者：
Swasti Tiwari;E. Blasi;J. Heyen;A. Mcharg;C. Ecelbarger
中科院分区：
文献类型：
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作者：
Swasti Tiwari;E. Blasi;J. Heyen;A. Mcharg;C. Ecelbarger
过氧化物酶体增殖物激活受体（PPAR-γ）激动剂可改善胰岛素敏感性，但与水肿相关。通过上皮钠通道（ENaC）和水通道蛋白-2（AQP-2）增加的远端小管钠和水重吸收已被认为起机制作用。为了确定这些蛋白质的分子调节，我们每天用溶剂、罗格列酮（RGZ，50 mg/kgbw）或PD 168（一种引起明显水肿的供试化合物，10 mg/kgbw）灌胃给药雄性Sprague-Dawley大鼠1、3或5天（n=6/治疗/次）。在第1天，RGZ显著降低尿钠排泄，PD 168的趋势较强（p值分别为0.047和0.053），表明早期钠潴留。RGZ或PD 168治疗12小时后血压降低。全肾匀浆（WKH）和膜富集部分（MF）的免疫印迹显示，两种药物在第1天时WKH中AQP-2的条带密度（29 kDa和糖基化条带）增加。然而，在第5天，29-kDa条带显著减少（溶剂的约30%）。RGZ在第3天增加了α-ENaC;然而，两种药物在第5天都降低了α-ENaC。相反，β-和γ-ENaC（85 kDa）在两种药物的作用下始终保持不变或降低。然而，在第3-5天，MF中γ-ENaC的70-kDa条带（活性条带）的密度被两种试剂增加（120-600%）。总体而言，这两种药物导致AQP-2和ENaC亚基带型的早期改变，其中许多被描述为活化变化。然而，随后AQP-2和α-ENaC的降低可能代表了重新建立钠和水平衡的尝试。
Peroxisome-proliferator-activated receptor (PPAR-γ) agonists improve insulin sensitivity, but are associated with edema. Increased distal tubule sodium and water reabsorption through the epithelial sodium channel (ENaC) and aquaporin-2 (AQP-2) have been suggested to play mechanistic roles. To determine the molecular regulation of these proteins, we treated male, Sprague–Dawley rats daily by gavage with either vehicle, rosiglitazone (RGZ, 50mg/kgbw), or PD168 (a test compound causing marked edema, 10mg/kgbw), for 1, 3, or 5 days (n=6/treatment/time). On day 1, urine sodium excretion was significantly reduced by RGZ with a strong trend for PD168 (p-values 0.047 and 0.053, respectively) indicating early sodium retention. Blood pressure was lowered by RGZ- or PD168 treatment by 12h. Immunoblotting of whole kidney homogenates (WKHs) and a membrane-enriched fraction (MF) revealed increased band densities for AQP-2 in WKH (29kDa and glycosylated bands) by both drugs at 1 day. However, at 5 days, the 29-kDa band was significantly decreased (∼30% of vehicle). α-ENaC was increased by RGZ at 3 days; however both agents decreased α-ENaC by 5 days. In contrast, β- and γ-ENaC (85kDa) were unchanged or decreased at all times by both agents. However, the 70-kDa band of γ-ENaC (active band) in MF was increased in density (120–600%) by both agents on days 3–5. Overall, both agents resulted in early alterations in banding patterns for AQP-2 and ENaC subunits, many of which are described as activating changes. However, later reduction in AQP-2 and α-ENaC may represent an attempt to re-establish sodium and water balance.