由 APOL1 高危变体 G1 和 G2 介导的肾病对血管紧张素转换酶抑制剂的敏感性不同。

IF 14.8 1区 医学 Q1 UROLOGY & NEPHROLOGY Kidney international Pub Date : 2024-08-23 DOI:10.1016/j.kint.2024.07.026
Esilida Sula Karreci, Sonako Jacas, Olivia Donovan, Diana Pintye, Nicholas Wiley, Zsuzsanna K Zsengeller, Johannes Schlondorff, Seth L Alper, David J Friedman, Martin R Pollak
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引用次数: 0

摘要

载脂蛋白 L1(APOL1)变体 G1 和 G2 会导致非洲裔个体罹患肾病的风险过高。由于疾病机制和最佳治疗方法仍存在争议,我们在 APOL1 肾病小鼠模型中研究了目前标准治疗药物的效果。实验在 APOL1 BAC 转基因小鼠中进行,这些小鼠在注射不含 pCpG 的 IFNɤ 质粒后出现蛋白尿和肾小球硬化。对注射了质粒的蛋白尿 G1/G1 和 G2/G2 小鼠随机进行药物治疗或不治疗。从第七天开始,利辛普利、达帕利嗪和水蛭素在饮用水中给药。每周测量两次尿白蛋白/肌酐比值,并对肾脏进行组织学检查,根据周期性酸-希夫染色切片计算局灶节段性肾小球硬化评分。标准剂量的血管紧张素转换酶抑制剂利辛普利可使 APOL1 G1/G1 BAC 转基因小鼠的蛋白尿减少约 90 倍,并减轻肾小球硬化。这些效果与血压无关。达帕格列净并未改变 G1/G1 或 G2/G2 小鼠的疾病进展。减少 G2/G2 BAC 转基因小鼠的蛋白尿和肾小球硬化所需的利辛普利剂量是对 G1/G1 小鼠有效剂量的两倍,但获得的益处却小得多。因此,在这些 BAC 转基因小鼠 APOL1 疾病模型中,与 G2/G2 APOL1 小鼠相比,标准剂量的利辛普利对 G1/G1 小鼠的抗蛋白尿和抗肾小球硬化效果显著。而通过肼屈嗪治疗降低血压并不能提供这种保护。钠-葡萄糖共转运体-2抑制剂达帕格列净对G1/G1或G2/G2小鼠均无改善。因此,患者对 ACE 抑制剂的反应是否存在类似差异仍有待确定。
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Differing sensitivities to angiotensin converting enzyme inhibition of kidney disease mediated by APOL1 high-risk variants G1 and G2.

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.

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来源期刊
Kidney international
Kidney international 医学-泌尿学与肾脏学
CiteScore
23.30
自引率
3.10%
发文量
490
审稿时长
3-6 weeks
期刊介绍: Kidney International (KI), the official journal of the International Society of Nephrology, is led by Dr. Pierre Ronco (Paris, France) and stands as one of nephrology's most cited and esteemed publications worldwide. KI provides exceptional benefits for both readers and authors, featuring highly cited original articles, focused reviews, cutting-edge imaging techniques, and lively discussions on controversial topics. The journal is dedicated to kidney research, serving researchers, clinical investigators, and practicing nephrologists.
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