Apolipoprotein L1 (APOL1) variants G1 and G2 contribute to the excess risk of kidney disease in individuals of recent African ancestry. Since disease mechanisms and optimal treatments remain controversial, we study the effect of current standard-of-care drugs in mouse models of APOL1 kidney disease. Experiments were performed in APOL1 BAC-transgenic mice, which develop proteinuria and glomerulosclerosis following injection with a pCpG-free IFN-γ plasmid. Proteinuric, plasmid injected G1/G1 and G2/G2 mice were randomized to drug treatment or no treatment. Lisinopril, dapagliflozin, and hydralazine were administered in drinking water starting day seven. The urine albumin/creatinine ratio was measured twice weekly, and the kidneys examined histologically with the focal segmental glomerulosclerosis score computed from periodic acid-Shiff-stained sections. The angiotensin converting enzyme inhibitor lisinopril, at standard dose, reduced proteinuria by approximately 90-fold and reduced glomerulosclerosis in the APOL1 G1/G1 BAC-transgenic mice. These effects were independent of blood pressure. Dapagliflozin did not alter disease progression in either G1/G1 or G2/G2 mice. Proteinuria reduction and glomerulosclerosis in G2/G2 BAC-transgenic mice required lisinopril doses two times higher than were effective in G1/G1 mice but achieved a much smaller benefit. Therefore, in these BAC-transgenic mouse models of APOL1 disease, the anti-proteinuric and anti-glomerulosclerotic effects of standard dose lisinopril were markedly effective in G1/G1 compared with G2/G2 APOL1 mice. Comparable reduction in blood pressure by hydralazine treatment provided no such protection. Neither G1/G1 nor G2/G2 mice showed improvement with the sodium-glucose cotransporter-2 inhibition dapagliflozin. Thus, it remains to be determined if similar differences in ACE inhibitor responsiveness are observed in patients.

中文翻译：

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对 APOL1 高危变异 G1 和 G2 介导的肾脏疾病血管紧张素转换酶抑制的不同敏感性


载脂蛋白 L1 （APOL1） 变体 G1 和 G2 导致近期非洲血统的个体患肾病的风险过高。由于疾病机制和最佳治疗仍然存在争议，我们研究了当前标准护理药物对 APOL1 肾病小鼠模型的影响。在 APOL1 BAC 转基因小鼠中进行了实验，该小鼠在注射不含 pCpG 的 IFN-γ质粒后出现蛋白尿和肾小球硬化。蛋白尿、质粒注射的 G1/G1 和 G2/G2 小鼠随机接受药物治疗或不治疗。从第 7 天开始，在饮用水中施用赖诺普利、达格列净和肼屈嗪。每周测量 2 次尿白蛋白/肌酐比值，使用由高碘酸 Shiff 染色切片计算的局灶节段性肾小球硬化评分进行组织学检查。标准剂量的血管紧张素转换酶抑制剂赖诺普利使 APOL1 G1/G1 BAC 转基因小鼠的蛋白尿减少约 90 倍，并减少了肾小球硬化。这些影响与血压无关。达格列净不改变 G1/G1 或 G2/G2 小鼠的疾病进展。G2/G2 BAC 转基因小鼠的蛋白尿减少和肾小球硬化所需的赖诺普利剂量比 G1/G1 小鼠有效剂量高两倍，但获得的益处要小得多。因此，在这些 APOL1 疾病的 BAC 转基因小鼠模型中，与 G2/G2 APOL1 小鼠相比，标准剂量赖诺普利的抗蛋白尿和抗肾小球硬化作用在 G1/G1 中显着有效。肼屈嗪治疗对血压的类似降低没有提供这种保护。G1/G1 和 G2/G2 小鼠均未显示出钠-葡萄糖协同转运蛋白-2 抑制达格列净的改善。 因此，在患者中是否观察到 ACE 抑制剂反应性存在类似差异仍有待确定。