Fardella C E, Rodriguez H, Montero J, Zhang G, Vignolo P, Rojas A, Villarroel L, Miller W L
Department of Pediatrics, University of California, San Francisco 94143, USA.
J Clin Endocrinol Metab. 1996 Dec;81(12):4347-51. doi: 10.1210/jcem.81.12.8954040.
Low renin hypertension (LRH), which accounts for 10-20% of patients with idiopathic "essential" hypertension, bears hormonal similarities to mineralocorticoid-induced hypertension, but elevated mineralocorticoid concentrations have not been found. Some patients with LRH have normal, rather than suppressed, plasma aldosterone concentrations, so that the ratio of aldosterone concentration to PRA (Aldo/PRA) is high, suggesting inappropriately increased aldosterone biosynthesis. We characterized the CYP11B2 gene that encodes the aldosterone synthase, P450c11AS, in hypertensive and control populations in a single clinic in Santiago, Chile. We directly sequenced the entire CYP11B2 gene in 12 patients with LRH, 2 high renin hypertensive controls, and 2 normotensive controls. All sequences were identical, except that 8 of 24 LRH alleles encoded arginine rather than lysine at position 173. The Arg173 and Lys173 variants were expressed in transfected MA-10 cells, and their ability to convert deoxycorticosterone to aldosterone was measured; the apparent Michaelis constant (Km) for Lys173 was 2.73 mumol/L; the Km for Arg173 was 2.53 mumol/L. The apparent maximal velocity (Vmax) for Lys173 was 6.5 x 10(-3) micrograms/mL.24 h; the Vmax for Arg173 was 7.8 x 10(-3) micrograms/mL.24 h. The first order rate constant, Vmax/Km was 2.38 for Lys173 and 3.08 for Arg173. As these values were not significantly different, we sought to determine whether Arg173 is a polymorphism linked to LRH. We examined position 173 in 52 unselected patients with idiopathic hypertension and 55 normotensive controls by PCR amplification of CYP11B2 exons 3-5 followed by digestion with Bsu361, which digests the Arg173 sequence, but not the Lys173 sequence. More of the hypertensive alleles (39 of 104, 37.5%) than normotensive alleles (25 of 110, 22.5%) carried Arg173 (chi 2 = 5.57; P < 0.02). Most of the Arg173 alleles (31 of 72, 43.1%) were from hypertensive patients with Aldo/PRA below 30, whereas only 5 of 24 (20.8%) Arg173 alleles were found in patients with Aldo/PRA greater than 30 (chi 2 = 3.79; P = 0.05) Thus, the ARg173 variant of CYP11B2 may be linked to LRH in Chilean patients.
低肾素性高血压（LRH）占特发性“原发性”高血压患者的10% - 20%，其激素特征与盐皮质激素诱导的高血压相似，但未发现盐皮质激素浓度升高。一些LRH患者的血浆醛固酮浓度正常而非被抑制，因此醛固酮浓度与肾素活性比值（Aldo/PRA）较高，提示醛固酮生物合成异常增加。我们在智利圣地亚哥的一家诊所对高血压人群和对照人群中编码醛固酮合酶P450c11AS的CYP11B2基因进行了特征分析。我们对12例LRH患者、2例高肾素性高血压对照者和2例血压正常对照者的整个CYP11B2基因进行了直接测序。所有序列均相同，只是24个LRH等位基因中有8个在第173位编码精氨酸而非赖氨酸。将第173位精氨酸（Arg173）和赖氨酸（Lys173）变体转染至MA - 10细胞中表达，并测定其将脱氧皮质酮转化为醛固酮的能力；Lys173的表观米氏常数（Km）为2.73 μmol/L；Arg173的Km为2.53 μmol/L。Lys173的表观最大反应速度（Vmax）为6.5×10⁻³ μg/mL·24 h；Arg173的Vmax为7.8×10⁻³ μg/mL·24 h。一级速率常数Vmax/Km，Lys173为2.38，Arg173为3.08。由于这些值无显著差异，我们试图确定Arg173是否为与LRH相关的多态性。我们通过PCR扩增CYP11B2外显子3 - 5，随后用Bsu361酶切（该酶可切割Arg173序列，但不能切割Lys173序列），检测了52例未经选择的特发性高血压患者和55例血压正常对照者的第173位。高血压等位基因（104个中有39个，37.5%）携带Arg173的比例高于血压正常等位基因（110个中有25个，22.5%）（χ² = 5.57；P < 0.02）。大多数Arg173等位基因（72个中有31个，43.1%）来自Aldo/PRA低于30的高血压患者，而在Aldo/PRA大于30的患者中仅发现24个Arg173等位基因中的5个（20.8%）（χ² = 3.79；P = 0.05）。因此，CYP11B2基因的Arg173变体可能与智利患者的LRH相关。
