Approximately 40% of patients with diabetes will develop diabetic kidney disease (DKD). Not only is it the leading cause of renal disease, but it is also associated with increased risk of patient morbidity and mortality. The diabetic milieu causes stress and injury to podocytes, glomerular epithelial cells, resulting in proteinuria and renal dysfunction. Thus, podocytes are key target cells that determine DKD progression; however, our limited understanding of podocyte signaling restricts our ability to develop cell-specific targeted therapy. We recently identified that ARF6 (ADP-ribosylation factor 6), a small GTPase protein, is involved with podocyte response to glomerular stress and deletion of ARF6 might be protective against podocyte damage in certain cases of kidney injury. The overall objective of this application is to define the role of ARF6 in DKD progression. This rationale is two-fold. First, increased ARF6 activity in other glomerular disease models mediates signaling pathways that result in effacement (i.e. a morphological adaptation seen in injured podocytes), and second, our preliminary data suggests that high glucose increases ARF6 activity. Thus, we hypothesize that hyperglycemia increases ARF6 activity which contributes to the progression of DKD. To this end, we will utilize diabetic models in vitro to determine if ARF6 has a role in podocyte effacement, detachment, and/or cell death. We will also identify the ARF6-GEFs (ARF6-guanine nucleotide exchange factors) that activate ARF6 by catalyzing ARF6-GDP to -GTP involved in effacement, detachment, and/or cell death. Using diabetic mice, we will specifically delete ARF6 from podocytes and determine the role of ARF6 in DKD. Last, we will explore pharmacologic interventions: ARF6 and ARF6-GEF inhibitors, to determine if ARF6 inhibition can prevent or augment DKD progression. Career Development Plan: The primary objective of this application is to support Dr. Lin?s career development into an independent physician-scientist in the area of cell signaling and molecular biology. Dr. Lin?s proposed training activities are in four areas 1) cell biology and signaling, 2) molecular techniques and genome editing, 3) diabetic mouse models of kidney injury, 4) scientific writing and oral presentations. Dr. Lin has assembled an exemplary mentoring and advisory team led by Dr. Farhad Danesh, Chief of Nephrology at MD Anderson Cancer Center (MDACC), a nationally recognized expert in the field of DKD and podocyte cell biology, complemented by Dr. Raghu Kalluri, Chair of Cancer Biology, Dr. Mien-Chie Hung, Chair of Molecular and Cellular Oncology, Dr. Elizabeth Shpall, Deputy Chair of Stem Cell Transplantation and Cellular Therapy, and Dr. David Tweardy, Head of the Division of Internal Medicine. MDACC, a center of excellence in cutting edge research, will provide an opportune, resource abundant training environment for Dr. Lin.
Podocyte injury is a pivotal event in diabetic kidney disease (DKD), the leading cause of chronic and end-stage kidney failure in the U.S. Small GTPase proteins, like ARF6 (ADP-ribosylation factor 6) play a key role in podocyte response to kidney injury. In this proposal, we will explore the contribution of ARF6 to the progression of DKD in hopes to identify new molecular targets to prevent or ameliorate kidney disease from diabetes.
