Riazi Shahla, Khan Osman, Tiwari Swasti, Hu Xinqun, Ecelbarger Carolyn A
Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, DC 20057-1412, USA.
Am J Nephrol. 2006;26(3):245-57. doi: 10.1159/000093783. Epub 2006 Jun 2.
BACKGROUND/AIMS: Progressive diabetes is associated renal remodeling, which we previously showed correlated to reduced protein abundance of several major renal sodium transporters and channel subunits in the obese Zucker rat. Here we test whether rosiglitazone (RGZ), a peroxisome proliferator-activated subtype gamma receptor agonist, would be protective and attenuate these changes.
Male, obese and lean Zucker rats (9 weeks old) were randomly divided (n = 6/group) to receive control diet with or without RGZ at 3 mg/kg.bw/day for 12 weeks.
RGZ normalized blood glucose and plasma fructosamine levels in obese rats. Obese control rats had relatively increased fractional excretion of sodium (FE(Na), sodium excretion relative to creatinine). Nonetheless, both obese and RGZ-treated rats had relatively higher 24-hour net sodium balances. Immunoblotting revealed obese rats had significantly reduced renal cortical protein abundances of the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and the sodium hydrogen exchanger (NHE3). RGZ normalized NKCC2 abundance and increased the abundance of the alpha-subunit of the epithelial sodium channel (ENaC). In contrast, in the outer medulla, obese rats had increased abundance of NKCC2, gamma-ENaC (85-kDa), and endothelial NOS. Furthermore, RGZ caused a decrease in the abundance of cortical beta- and gamma-ENaC (85-kDa). Finally, the whole kidney abundances of alpha-1 Na-K-ATPase, alpha- beta-, and gamma-ENaC (70-kDa band) positively correlated with net sodium balance, whereas NKCC2 was negatively correlated to FE(Na).
Chronic RGZ treatment of obese Zucker rats may preserve renal sodium reabsorptive capacity by its indirect actions to attenuate hyperglycemia as well as direct effects on transporter abundance and activity.
背景/目的：进行性糖尿病与肾脏重塑有关，我们之前发现肥胖Zucker大鼠中几种主要肾钠转运体和通道亚基的蛋白丰度降低与此相关。在此，我们测试过氧化物酶体增殖物激活受体γ亚型激动剂罗格列酮（RGZ）是否具有保护作用并减轻这些变化。
将雄性、肥胖和瘦的Zucker大鼠（9周龄）随机分组（每组n = 6），给予含或不含3 mg/kg体重/天RGZ的对照饮食，持续12周。
RGZ使肥胖大鼠的血糖和血浆果糖胺水平恢复正常。肥胖对照大鼠的钠分数排泄（FE(Na)，钠排泄相对于肌酐）相对增加。尽管如此，肥胖大鼠和接受RGZ治疗的大鼠24小时净钠平衡均相对较高。免疫印迹显示，肥胖大鼠肾皮质中布美他尼敏感的Na-K-2Cl共转运体（NKCC2）和钠氢交换体（NHE3）的蛋白丰度显著降低。RGZ使NKCC2丰度恢复正常，并增加了上皮钠通道（ENaC）α亚基的丰度。相反，在外髓质中，肥胖大鼠的NKCC2、γ-ENaC（85 kDa）和内皮型一氧化氮合酶丰度增加。此外，RGZ导致皮质β-和γ-ENaC（85 kDa）丰度降低。最后，α-1 Na-K-ATP酶、α-、β-和γ-ENaC（70 kDa条带）的全肾丰度与净钠平衡呈正相关，而NKCC2与FE(Na)呈负相关。
对肥胖Zucker大鼠长期给予RGZ治疗可能通过间接减轻高血糖以及对转运体丰度和活性的直接作用来维持肾脏钠重吸收能力。
