Tubular proteinuria resulting from impaired endocytic uptake of filtered proteins by the kidney proximal tubule (PT) is a common feature of early kidney dysfunction that poses a significant risk for development of end-stage renal disease. This proposal aims to understand the mechanistic basis of Dent disease, a progressive genetic disorder characterized by tubular proteinuria that is caused by mutations in the 2Cl-/H+ exchanger ClC-5. Enhanced degradation of megalin, a multiligand co-receptor that binds to filtered proteins, is thought to underlie the tubular proteinuria in Dent disease, however, the step in trafficking that is affected is unknown, and the contribution of pH vs. Cl- homeostasis to the disease phenotype is disputed. We will utilize a combination of genetic, morphological, mathematical modeling, and biochemical approaches to accomplish the following aims: (1) identify the step(s) in membrane traffic that are impaired in ClC-5 knockdown PT cells; (2) determine the molecular mechanism that links loss of ClC-5 to reduced megalin expression; and (3) identify therapeutic targets for restoring megalin expression and function in a mouse model of Dent disease.
A major function of the proximal tubule of the kidney is to recover proteins that enter the nephron to prevent their escape in the urine. Defective proximal tubule function as a result of genetic mutations or kidney injury leads to tubular proteinuria that can progress to end stage renal disease. Our studies here focus on understanding how mutations in an ion transporter that is mutated in Dent disease leads to impaired protein recovery by the proximal tubule. The results of our research will provide important new information about the mechanism of protein recovery that may help in designing therapies for tubular proteinuria.
