Uncovering The Potential of Proximal Tubule Cells for Disease Modeling and Therapeutic Interventions

Abstract

This thesis focused on uncovering the intricate interactions between the proximal tubule (PT) and disease mediators through the development and application of in vitro models. For this, we extensively reviewed the currently available PT in vitro models, followed by the application of a series of in vitro PT models designed to address the factors contributing to injury. Our initial focus was on understanding the interactions between uremic toxins (UTs), particularly those bound to albumin (PBUTs), and drugs prescribed for treatment of CKD complications. Our findings revealed that certain drugs, including angiotensin receptor blockers and the diuretic, furosemide, may inadvertently compromise PBUTs uptake, thus leading to their accumulation and kidney function deterioration. Additionally, this finding has implications in the efficacy of the bioartificial kidney (BAK), designed to complement conventional dialysis by removing PBUTs. To advance its clinical application, we investigated the performance of a BAK functional unit in conditions that mimic dialysis. Our results showed that dialysis fluid, a solution used in dialysis to aid waste product removal and maintain patients’ electrolyte levels, is cytocompatible with the BAK-containing cells and does not interfere with PBUTs clearance. Furthermore, given the high mitochondrial density found in PT required for ATP production, and needed for transport and metabolism functions, we explored the implications of impaired mitochondrial function, as a result of ischemia and hyperglycemia. In response to this damage, we employed therapeutic strategies, including stem cell therapy and diabetes medication. Our findings showcase that stem cell therapy successfully restored the bioenergetic profile of ischemic PT cells, while a diabetes drug effectively reduced the secretion of kidney injury markers. Altogether, the comprehensive findings of this thesis contribute to an enhanced understanding of the PT as a prime target for disease modeling and the development of targeted therapeutic interventions.