Tornavaca O, Pascual G, Barreiro M L, Grande M T, Carretero A, Riera M, Garcia-Arumi E, Bardaji B, González-Núñez M, Montero M A, López-Novoa J M, Meseguer A
Fisiopatologia Renal, Centre d'Investigacions en Bioquímica i Biologia Molecular, Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Circulation. 2009 Apr 14;119(14):1908-17. doi: 10.1161/CIRCULATIONAHA.108.808543. Epub 2009 Mar 30.
Kidney androgen-regulated protein (KAP), a proximal tubule androgen-regulated gene, codes for a protein of unknown function.
To investigate the consequences of KAP overexpression in kidney, we produced KAP transgenic mice and performed microarray expression analyses in kidneys of control and transgenic males. Downregulation of the androgen-sensitive Cyp4A14 monooxygenase gene in KAP transgenic mice prompted us to analyze blood pressure levels, and we observed that transgenic mice were hypertensive. Inhibition of 20-hydroxyeicosatetraenoic acid synthesis by N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) reduced the increased 20-hydroxyeicosatetraenoic acid levels in urine and normalized arterial pressure in transgenic mice, as did the NADPH oxidase inhibitor apocynin. Increased oxidative stress in transgenic mice was demonstrated by (1) enhanced excretion of urinary markers of oxidative stress, 8-iso-prostaglandin F2alpha, 8-hydroxydeoxyguanosine, and thiobarbituric acid-reacting substances; (2) augmented mitochondrial DNA damage and malondialdehyde levels in kidneys; and (3) diminished catalase and glutathione peroxidase activity in transgenic kidneys. Mice exhibited renal defects that included focal segmental glomerulosclerosis, proteinuria, glycosuria, and fibrosis.
Taken together, these results indicate that KAP expression is critical for cardiovascular-renal homeostasis maintenance and that hypertension is associated with increased oxidative stress. This is the first report showing that overexpression of an androgen-regulated, proximal tubule-specific gene induces hypertension. These observations may shed light on the molecular pathophysiology of gender differences in the prevalence and severity of hypertension and chronic renal disease.
肾雄激素调节蛋白（KAP）是一种近端小管雄激素调节基因，编码一种功能未知的蛋白质。
为了研究KAP在肾脏中过表达的后果，我们制备了KAP转基因小鼠，并对对照和转基因雄性小鼠的肾脏进行了微阵列表达分析。KAP转基因小鼠中雄激素敏感的Cyp4A14单加氧酶基因的下调促使我们分析血压水平，我们观察到转基因小鼠患有高血压。N-羟基-N'-（4-正丁基-2-甲基苯基）甲脒（HET0016）抑制20-羟基二十碳四烯酸合成可降低转基因小鼠尿液中升高的20-羟基二十碳四烯酸水平并使动脉压恢复正常，烟酰胺腺嘌呤二核苷酸磷酸氧化酶抑制剂夹竹桃麻素也有同样效果。转基因小鼠氧化应激增加表现为：（1）氧化应激尿标志物8-异前列腺素F2α、8-羟基脱氧鸟苷和硫代巴比妥酸反应物质的排泄增加；（2）肾脏中线粒体DNA损伤和丙二醛水平升高；（3）转基因肾脏中过氧化氢酶和谷胱甘肽过氧化物酶活性降低。小鼠表现出肾脏缺陷，包括局灶节段性肾小球硬化、蛋白尿、糖尿和纤维化。
综上所述，这些结果表明KAP表达对于维持心血管-肾脏稳态至关重要，高血压与氧化应激增加有关。这是第一份表明雄激素调节的近端小管特异性基因过表达会诱发高血压的报告。这些观察结果可能有助于阐明高血压和慢性肾病患病率及严重程度性别差异的分子病理生理学。
