Abstract：
The efficient reabsorption of essential nutrients by epithelial cells in the proximal tubule of the kidney is crucial for maintaining homeostasis. This process relies heavily on a complex ecosystem of vesicular trafficking pathways. At the center of this network, the lysosome plays a pivotal role in processing incoming molecules, sensing nutrient availability, sorting receptors and transporters, and balancing differentiation and proliferation in the tubular epithelial cells. Disruptions in these fundamental processes can lead to proximal tubulopathy-a condition characterized by the dysfunction of the tubular cells followed by the presence of low-molecular-weight proteins and solutes in urine. If left untreated, proximal tubulopathy can progress to chronic kidney disease and severe complications. Functional studies of rare inherited disorders affecting the proximal tubule have gleaned actionable insights into fundamental mechanisms of homeostasis while revealing drug targets for therapeutic discovery and development. In this mini review, we explore hereditary proximal tubulopathies as a paradigm of kidney homeostasis disorders, discussing the factors contributing to tubular dysfunction. In addition, we shed light on the current landscape of drug discovery approaches used to identify actionable targets and summarize the preclinical pipeline of potential therapeutic agents. These efforts may ultimately lead to new treatment avenues for proximal tubulopathies, which are currently inadequately tackled by existing therapies. Through this article, our hope is to promote academia-industry partnerships and advocate for research consortia that can accelerate the effective translation of knowledge advances into innovative therapies addressing the huge unmet needs of individuals with these debilitating diseases.
摘要：
肾脏近端小管中上皮细胞对必需营养素的有效再吸收对于维持稳态至关重要。该过程严重依赖于囊泡运输途径的复杂生态系统。在这个网络的中心，溶酶体在处理进来的分子中起着关键作用，感知养分的可用性，分选受体和转运蛋白，平衡肾小管上皮细胞的分化和增殖。这些基本过程的破坏可导致近端肾小管病-一种以肾小管细胞功能障碍为特征的疾病，随后在尿液中存在低分子量蛋白质和溶质。如果不及时治疗，近端肾小管病可进展为慢性肾脏病和严重并发症。对影响近端小管的罕见遗传性疾病的功能研究已经收集了对稳态基本机制的可行见解，同时揭示了治疗发现和开发的药物靶标。在这个迷你评论中，我们探索遗传性近端肾小管病变作为肾脏稳态障碍的范例，讨论导致肾小管功能障碍的因素。此外,我们揭示了用于确定可操作靶标的药物发现方法的现状，并总结了潜在治疗药物的临床前流程。这些努力可能最终导致近端肾小管病变的新治疗途径，目前现有的疗法无法充分解决。我们的希望是,通过这篇文章,促进学术界与工业界的伙伴关系，并倡导研究联盟，以加速将知识进步有效转化为创新疗法，以解决患有这些使人衰弱的疾病的个人的巨大未满足的需求。
