Supported Research

Co-Applicant(s):  Mathieu Lemaire

Lay Abstract

BACKGROUND: High blood pressure, or hypertension, affects about 30% of the people in the world. The kidney plays a critical role in regulating blood pressure by controlling the balance of ions and water in the body. These processes are influenced by hormones in our bloodstream. Key players in this regulation are several ion channels and transporters found in the kidney, like ENaC, NCC, NKCC2 and NHE3. Our research has focused on ENaC, which we found is regulated by a process called ubiquitination, primarily by an enzyme called NEDD4L. Ubiquitination is a way to mark proteins for breakdown. NEDD4L binds to ENaC, tags it with ubiquitin, and sends it for degradation. When there are mutations in ENaC that prevent it from binding to NEDD4L, it leads to a rare condition called Liddle syndrome, causing high blood pressure (hypertension), usually detected already in children. Recently, we discovered a Liddle syndrome patient with normal ENaC but mutations in NEDD4L. Our studies showed that these mutations severely reduce NEDD4L activity, preventing ENaC from being degraded. This explains why this patient has Liddle syndrome, marking the first case of Liddle syndrome caused by NEDD4L mutations instead of ENaC mutations. We are now studying more Liddle syndrome patients with normal ENaC to see if they also have NEDD4L mutations. Importantly, NEDD4L was also found to affect the stability of other kidney-resident proteins that regulate blood pressure, namely NCC, NKCC2 and NHE3. So, our discovery suggests that NEDD4L should be considered in genetic screenings for high blood pressure control. While Liddle syndrome is rare, hypertension is widespread. In our analysis of a large genetic database (GnomAD) with over 800,000 people, we found variations in the NEDD4L gene in different populations, including Europeans, African Americans, and South Asians. We don't yet know how these variations affect NEDD4L's function or its regulation of target proteins. RESEARCH GOALS: Our research has two main goals: (i) To study the function of NEDD4L variations associated with high or low blood pressure in different populations. (ii) To identify the kidney-related targets of NEDD4L variants that affect its function, especially ENaC, NCC, NKCC2 and NHE3, including their ubiquitination, stability, and their ion/water transport functions. OUR APPROACH: We will use genetic, biochemical, and cell biology methods, leveraging our expertise in these areas. Dr. Rotin specializes in the ubiquitin field, particularly the NEDD4 family and its effects on membrane proteins like ENaC and NKCC. Dr. Lemaire is a nephrologist with expertise in genetic kidney diseases. EXPECTED OUTCOME: We expect that harmful NEDD4L mutations will play a crucial role in blood pressure regulation, especially in hypertension. PATIENTS INVOLVEMENT: We obtained publicly available sequence data from patients with their consent. SIGNIFICANCE: Our research will reveal how NEDD4L and ubiquitination control blood pressure in different populations. It may lead to personalized treatments based on the specific kidney targets affected by mutant NEDD4L.