Research Awards Recipients

Lay Abstract

Kidneys act as a barrier that filters water and waste products into urine while retaining important proteins in blood. When this filtration barrier is impaired, massive leakage of proteins into urine (proteinuria) occurs, leading to a condition known as nephrotic syndrome. Regardless of the cause, nephrotic syndrome all have one thing in common, namely damage to a specialized cell called “podocytes”, which is an important constituent of the filtration barrier. Minimal change disease (MCD) is a common cause of nephrotic syndrome in children and it also affects adults of all ages. In spite of intense research for 5 decades, the precise cause of MCD is still unknown, preventing us from identifying specific treatments. To understand how a disease occurs, it is helpful to have an animal model that mimics the human disease. A major limitation of the MCD research is that currently, there is no good animal model of MCD. Patients with MCD respond to non-specific immuno-suppressive drugs such as glucocorticoids. Therefore, dysfunctional immune system is most certainly a cause of MCD. However, the immune system is complex involving many different cell types and it is unknown which cells are responsible for the disease. It has been believed for a long time that in MCD, inappropriately activated T lymphocytes produce some factor(s), which reach the kidney via circulation and injure podocytes. More recently, it was found that an immune-suppressant called rituximab that targets and inhibits B lymphocytes is effective in preventing disease relapse of MCD. This clinical observation, combined with several research data, now strongly suggests that B lymphocytes and antibodies they produce may also play an important role in causing MCD. Recently, we discovered a novel mouse model which resembles the clinical picture and kidney histology of human MCD. This model is induced by injecting mice with a recombinant protein representing part of the protein called Crb2, which is normally expressed in podocytes. We hypothesize that the immune system of the mouse responds to the injected Crb2 protein and activated T and B lymphocytes cause podocyte injury either directly or via antibodies. We will study the immune response in the mouse injected with Crb2 protein and how the changes in the immune system lead to podocyte injury. If successful, the study will establish an immune mechanism-based mouse model of MCD, which is currently missing. Our ultimate goal will be to study if similar mechanisms are responsible in patients with MCD and finally, identify the precise cellular and molecular therapeutic targets in patients with MCD. We have a parallel study to analyze lymphocytes from patients with MCD, thus the results of the current study will be compared to human data to address clinical relevance of the findings in mice.