Intracellular functions of APOL1 in the kidney

摘要 非裔美国人的慢性肾脏病(CKD)是美国最大的种族健康差距之一。风险增加的原因被归因于载脂蛋白L1(APOL1)基因中等位基因变异的隐性遗传。这些被称为G1和G2的APOL1变体本身不会导致CKD，但CKD是由遗传遗传风险和暴露于触发环境应激源的组合引起的。APOL1在肾脏中的生物学功能以及在疾病应激源背景下的发病机制尚不清楚。我们最近的研究首次证明了常见的APOL1等位基因G0在预防足细胞丢失和肾小球硬化方面的功能，这种疾病与APOL1风险等位基因(HIV相关肾病)的携带高度相关。这种保护的根本原因似乎与APOL1 G0通过模式识别受体支持先天性免疫信号事件的作用有关。此外，由于APOL1风险是一种隐性遗传特征，这也表明CKD可能部分是由于这一有益功能的丧失造成的。为了推进这些研究，我们建议开发额外的基于细胞和动物的模型系统来研究APOL1 G0在先天性免疫反应中的功能，以及这些反应在风险变量G1和G2存在时是如何改变的。这些基于细胞和动物的新系统将允许生化研究探讨作用机制，允许生理研究评估对CKD进展的影响，并应提供与APOL1风险等位基因隐性遗传相关的获得与功能丧失机制的洞察力。确定G0功能对风险变量功能障碍的贡献将对进一步的治疗设计产生重要的临床影响，因为它将确定替代G0或抑制风险变量将是更有效的策略。

ABSTRACT Chronic kidney disease (CKD) in African Americans is one of the largest racial health disparities in the United States. The cause for the increased risk has been attributed to recessive inheritance of allelic variants in the gene for apolipoprotein L1 (APOL1). These APOL1 variants, known as G1 and G2, do not cause CKD on their own, but CKD is caused by a combination of the inherited genetic risk plus exposure to a triggering environmental stressor. The biological function of APOL1 in the kidney and the mechanism of pathogenesis in the setting of a disease stressor remain unclear. Our recent studies have demonstrated, for the first time, a function for the common APOL1 allele, known as G0, in providing protection against podocyte losses and glomerulosclerosis in one of the CKDs highly associated with carriage of APOL1 risk alleles (HIV-associated nephropathy). The fundamental cause of this protection appears to be linked to a role of APOL1 G0 in supporting innate immune signaling events through pattern recognition receptors. In addition, since APOL1 risk is a recessively inherited trait, this also suggests CKD may be cause, in part, by a loss of this beneficial function. To advance these studies, we propose to develop additional cell-based and animal-based model systems to investigate the function of APOL1 G0 in innate immune responses, and how these responses are altered in the presence of the risk variants G1 and G2. These new cell and animal based systems will allow for both biochemical studies to address mechanism of action and physiological studies to assess impact on CKD progression, and should provide insight into gain- versus loss-of-function mechanisms associated with the recessive inheritance of APOL1 risk alleles. Determining the contribution of G0 function versus risk variant dysfunction will have important clinical impact on further therapy design, as it will establish whether replacement of G0 or suppression of the risk variants would be the more effective strategy.