End-stage kidney disease (ESKD) is the ninth-leading cause of death in the United States. The majority of incident ESKD is attributed to diabetic and hypertensive kidney disease. The progression of these kidney diseases is strongly associated progressive pathophysiological changes of the kidney microvasculature. Despite the recognized importance of vascular dysfunction in kidney diseases, the mechanisms by which pathologic changes occur and how they contribute to disease progression remains poorly understood. Developmental mechanisms are frequently reactivated during kidney disease and tissue repair, making it essential to first address knowledge gaps in our understanding of renal vascular development. These major knowledge gaps must be filled to permit development of targeted vascular therapies and accelerate development of bioengineered kidneys. Endothelial development and maintenance depend upon signaling activity of vascular endothelial growth factor receptors (VEGFRs). This receptor family is comprised of three receptors designated VEGFR 1-3. The most studied, VEGFR2 and its ligand VEGFA, are well established as an important regulator of blood vascular development and maintenance in the kidney, with disruption being causally linked to diseases including thrombotic microangiopathies and pre-eclampsia. Despite its central role in renal health, VEGFA and its receptor VEGFR2 are poor therapeutic targets due to an extremely narrow therapeutic window in the kidney. More recently, dysregulation of VEGFR3 activity has been causally linked to the development of kidney disease and proposed as an exciting candidate for future therapeutics. Increased expression of VEGFR3 coincides with the progression of diabetic kidney disease, renal fibrosis and cystogenesis and targeting VEGFR3 in these diseases states has been demonstrated to ameliorate progression of some forms of kidney disease. However, the mechanism(s) by which this pathway influences disease progression and the specific vascular structures involved, remain uncertain and debated. Our preliminary data reveals that VEGFR3, while typically associated with the lymphatic vasculature, is also expressed in specialized subpopulation of the kidney blood vasculature, including the endothelial cells of the glomerulus. Additionally, it has been proposed that VEGFR3 in the blood vasculature functions to modulate VEGFA/VEGFR2 signaling, which would have important implications for potential therapeutic targeting. We propose for the first time to perform a comprehensive evaluation of the function of VEGFR3 in the vascular beds of the kidney. This will include detailed expression mapping of VEGFR3 through kidney development, functional evaluation of VEGFR3 via a newly generated knockout mouse model, and evaluation of VEGFR3’s modulation of VEGFR2 signaling through both in vivo and ex vivo assays. Our proposal will provide fundamental new insights about the function of VEGFR3 in the kidney vasculature establishing the foundation for developing future vascular-targeted therapies for kidney disease.
|Effective start/end date||7/1/20 → 6/30/22|
- ASN Foundation for Kidney Research (AGMT 5/7/20)