Identification of novel oxygen-dependent interstitial molecular markers of renal disease progression
While molecular oxygen is a critical substrate for cellular oxidative processes, it also acts as an important signaling molecule that controls cellular plasticity and function. This has wide-ranging implications for the pathogenesis and treatment of kidney diseases. Specifically, we hypothesize that molecular oxygen acts as a signal that mediates the cross talk between different cell populations in the kidney, and thus impacts normal renal function and pathogenesis. A critical pathway through which molecular oxygen regulates cellular differentiation and function, is the prolyl-4-hydroxylase domain (PHD)/hypoxia-inducible factor (HIF) oxygen-sensing pathway. Our laboratory has shown that the severity of diabetic nephropathy correlates with HIF-1a expression levels in renal epithelial cells. However not much is known about the function of the PHD/HIF axis in the renal vasculature. Here, we examine the role of endothelial HIF signaling in the progression of diabetic nephropathy (DN) and investigate the molecular alterations that associate with HIF activation in renal endothelial cells. Aim 1 investigates the development of DN in mouse strains that either lack HIF-2 or PHD2 in endothelial cells. Aim 2 uses RNA sequencing technology for the identification and molecular characterization of renal EC subpopulations. Our studies aim at the identification of novel oxygen-dependent molecular markers that associate with the development of DN and renal disease progression and will provide novel insights into the heterogeneity and plasticity of renal EC during the development of DN.

Curation Flag Information