Dummer Patrick D, Limou Sophie, Rosenberg Avi Z, Heymann Jurgen, Nelson George, Winkler Cheryl A, Kopp Jeffrey B
Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Molecular Epidemiology Genetics Section, Center for Cancer Research, National Cancer Institute, Frederick MD.
Semin Nephrol. 2015 May;35(3):222-36. doi: 10.1016/j.semnephrol.2015.04.008.
Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.
载脂蛋白L1（APOL1）基因变异是导致慢性肾病和终末期肾病额外风险的主要原因，这在全球范围内造成了非洲裔人群显著的健康差距。我们估计，携带APOL1双风险等位基因的个体患肾病的终身风险至少为15%。实验证据表明，APOL1在肾损伤中的孔形成、细胞损伤和程序性细胞死亡中起直接作用。APOL1的BH3基序通常与细胞死亡相关，但不太可能在APOL1诱导的细胞毒性中发挥作用，因为它在APOL家族中不保守，且在体外细胞死亡中并非必需。我们讨论了APOL1抗锥虫活性的两种模型：一种涉及溶酶体通透性增加，另一种涉及细胞体的胶体渗透肿胀，以及它们与人类病理生理学的相关性。来自人类细胞培养模型的实验证据表明，这两种机制可能都起作用。一种系统生物学方法，即通过将受影响个体中与APOL1相关的基因和蛋白质表达扰动与分子途径相关联，可能有助于阐明APOL1在体内的功能。
