Drug discovery and therapeutic perspectives for proximal tubulopathies

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.