Grant: Project Grant

Collapsing glomerulopathy (CG) is an aggressive kidney disease that rapidly progresses to kidney failure. Although first recognized as a complication of uncontrolled HIV infection, doctors now know that CG can be triggered by other infections such as COVID-19, as well as by certain auto-immune diseases. Unfortunately, little is known about why and how CG occurs, and so no effective treatments exist. What is known is that people of recent African descent have a much higher risk of developing CG, at least in part because of a higher chance of having mutations in a gene called APOL1. Podocytes are specialized cells in the kidney that help filter blood to produce urine. In CG, podocytes proliferate in an uncontrolled manner, a process which is accompanied by rapid and extensive scarring of the kidney. How changes in APOL1 might cause these changes is not well understood. YAP and TAZ are two closely related proteins that promote cell proliferation and scarring. We have recently shown that the podocytes of people with APOL1 mutations and CG have hyperactive YAP and TAZ, as do the podocytes of mice which have the same APOL1 mutations seen in humans with CG. In this proposal, we will examine how APOL1 mutations can lead to YAP and TAZ activation, and how YAP/TAZ activation causes CG. Ultimately, we anticipate that our findings may inform the development of new treatment strategies for this devastating disease.