Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.
Mol Cell Biochem. 2010 Jan;333(1-2):203-9. doi: 10.1007/s11010-009-0220-4. Epub 2009 Jul 25.
Fructose feeding has been shown to induce insulin resistance and hypertension. Renal protein expression for the cytochrome P (CYP) 450 arachidonic acid metabolizing enzymes has been shown to be altered in other models of diet-induced hypertension. Of special interest is CYP4A, which produces the potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid and CYP2C, which catalyzes the formation of the potent dilators epoxyeicosatrienoic acids as well as soluble epoxide hydrolase (sEH) which metabolizes the latter to dihydroxyeicosatrienoic acids. The RhoA/Rho kinase (ROCK) signaling pathway is downstream of arachidonic acid and is reported to mediate metabolic-cardio-renal dysfunctions in some experimental models of insulin resistance and diabetes. The aim of the present study was to determine the expression of CYP4A, CYP2C23, CYP2C11, sEH, RhoA, ROCK-1, ROCK-2, and phospho-Lin-11/Isl-1/Mec-3 kinase (LIMK) in kidneys of fructose-fed (F) rats. Male Wistar rats were fed a high fructose diet for 8 weeks. Body weight, systolic blood pressure, insulin sensitivity, and renal expression of the aforementioned proteins were assessed. No change was observed in the body weight of F rats; however, euglycemia and hyperinsulinemia implicating impaired glucose tolerance and significant elevation in systolic blood pressure were observed. Renal expression of CYP4A and CYP2C23 was significantly increased while that of CYP2C11 and sEH was not changed in F rats. Equal expression for RhoA in both control and F rats and an enhanced level of ROCK-1 and ROCK-2 constitutively activate 130 kDa cleavage fragments as well as phospho-LIMK. These data suggest that the kidneys could be actively participating in the pathogenesis of insulin resistance-induced hypertension through the arachidonic acid CYP 450-RhoA/Rho kinase pathway(s).
果糖喂养已被证明可诱导胰岛素抵抗和高血压。在其他饮食诱导的高血压模型中，已显示肾细胞色素 P（CYP）450 花生四烯酸代谢酶的蛋白表达发生改变。特别引人关注的是 CYP4A，它产生强效血管收缩剂 20-羟二十碳四烯酸，CYP2C 催化强效扩张剂环氧二十碳三烯酸的形成，以及可溶性环氧化物水解酶（sEH），它将后者代谢为二羟二十碳三烯酸。RhoA/Rho 激酶（ROCK）信号通路位于花生四烯酸下游，据报道在一些胰岛素抵抗和糖尿病的实验模型中介导代谢-心脏-肾脏功能障碍。本研究的目的是确定果糖喂养（F）大鼠肾脏中 CYP4A、CYP2C23、CYP2C11、sEH、RhoA、ROCK-1、ROCK-2 和磷酸-Lin-11/Isl-1/Mec-3 激酶（LIMK）的表达。雄性 Wistar 大鼠给予高果糖饮食 8 周。评估体重、收缩压、胰岛素敏感性以及上述蛋白在肾脏中的表达。F 大鼠体重无变化；然而，观察到血糖正常和高胰岛素血症，提示糖耐量受损和收缩压显著升高。F 大鼠肾脏 CYP4A 和 CYP2C23 的表达显著增加，而 CYP2C11 和 sEH 的表达无变化。在对照和 F 大鼠中 RhoA 的表达相等，ROCK-1 和 ROCK-2 的水平增强，导致 130 kDa 切割片段以及磷酸-LIMK 的持续激活。这些数据表明，肾脏可能通过花生四烯酸 CYP 450-RhoA/Rho 激酶通路积极参与胰岛素抵抗诱导的高血压的发病机制。
