Singhal Pravin C, Skorecki Karl
Department of Medicine, Feinstein Institute for Medical Research, Zucker School of Medicine, Hempstead, NY 11549, USA.
Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel.
Biomolecules. 2025 Feb 1;15(2):205. doi: 10.3390/biom15020205.
APOL1 Renal Risk Variants (APOL1RRVs, G1, and G2) are known to be toxic to glomerular podocytes and causally associated with an enhanced prevalence and progression of many different etiologies of chronic kidney disease (CKD), leading to the delineation of a new disease designation of APOL1-Mediated Kidney Disease (AMKD). Notably, APOL1RRVs have not consistently been shown to increase the prevalence or severity of diabetic kidney disease (DKD) progression, which is the most common cause of End-Stage Kidney Disease (ESKD). While this apparent discrepancy seems perplexing, its clarification should provide important mechanistic and therapeutic insights. Activation of the Renin-Angiotensin System (RAS) plays a critical role in the development and progression of DKD. Recent in vitro and in vivo studies also demonstrated that RAS activation contributes to kidney cell injury in AMKD experimental models. Both high glucose, as well as APOL1RRVs escalate the podocyte expression of miR193a, a known mediator of glomerulosclerosis, including idiopathic Focal Segmental Glomerular Sclerosis (FSGS) and DKD. We propose that either the RAS and/or miR193a levels in the diabetic milieu are already maximally conducive to kidney target cell injury and, therefore, are agnostic to further injury in response to APOL1RRVs. Similarly, the contributory role of hypertension (which is frequently reported as the second most common cause of ESKD) in the progression of AMKD remains a controversial issue. Since several clinical reports have shown that controlling hypertension does not consistently slow the progression of AMKD, this has led to a formulation wherein APOL1-RRVs primarily lead to kidney injury with accompanying hypertension. Notably, half a decade later, the notion that hypertension is not a cause but rather a consequence of kidney injury was contested by investigators analyzing the Mount Sinai BioMe repository, a comprehensive clinical and genetic database including participants with APOL1RRVs. These investigators observed that hypertension predated the observed decline in GFR in individuals with APOL1RRVs by ten years. In the present study, we discuss the mechanistic forces that may underpin the gaps in these clinical manifestations, which did not allow the temporal association of hypertension with AMKD to be translated into causation and may also dissociate DKD and AMKD. We have hypothesized models that need to be validated in future experimental studies.
载脂蛋白L1肾脏风险变异体（APOL1RRVs，G1和G2）已知对肾小球足细胞有毒性，并与多种不同病因的慢性肾脏病（CKD）的患病率增加和病情进展有因果关系，从而产生了一种新的疾病命名——载脂蛋白L1介导的肾脏病（AMKD）。值得注意的是，APOL1RRVs并未始终如一地显示会增加糖尿病肾病（DKD）进展的患病率或严重程度，而DKD是终末期肾病（ESKD）最常见的病因。虽然这种明显的差异似乎令人困惑，但其阐明应能提供重要的机制和治疗见解。肾素 - 血管紧张素系统（RAS）的激活在DKD的发生和发展中起关键作用。最近的体外和体内研究还表明，RAS激活在AMKD实验模型中导致肾细胞损伤。高血糖以及APOL1RRVs都会使miR193a在足细胞中的表达增加，miR193a是肾小球硬化的已知介质，包括特发性局灶节段性肾小球硬化（FSGS）和DKD。我们提出，糖尿病环境中的RAS和/或miR193a水平已经最大程度地有利于肾脏靶细胞损伤，因此，对APOL1RRVs引起的进一步损伤不敏感。同样，高血压（经常被报道为ESKD的第二大常见病因）在AMKD进展中的作用仍然是一个有争议的问题。由于一些临床报告表明，控制高血压并不能始终如一地减缓AMKD的进展，这导致了一种观点，即APOL1 - RRVs主要导致肾脏损伤并伴有高血压。值得注意的是，五年后，分析西奈山生物医学数据库（一个包括APOL1RRVs参与者的综合临床和遗传数据库）的研究人员对高血压不是肾脏损伤的原因而是结果这一观点提出了质疑。这些研究人员观察到，高血压比APOL1RRVs个体中观察到的肾小球滤过率（GFR）下降早十年出现。在本研究中，我们讨论了可能是这些临床表现差异背后的机制因素，这些因素不允许将高血压与AMKD的时间关联转化为因果关系，也可能使DKD和AMKD分离。我们已经提出了一些模型，需要在未来的实验研究中进行验证。
