Hemodynamic forces play a crucial role in renal physiology and pathophysiology but the cellular and molecular mechanisms controlling the development of the specialized properties of the renal vascular bed remain poorly understood. We recently discovered that the Foxd1 lineage, which differentiates into pericytes, vascular smooth muscle, and the glomerular mesangium, plays a fundamental role in this process. Specifically, conditional ablation of the TALE transcription factor, Pbx1, in this lineage results in gross renal arterial patterning defects and premature death of mutant pups. Strikingly, conditional Pbx1 ablation does not markedly perturb renal epithelial morphogenesis. These data suggest that ablation of Pbx1 in the Foxd1 lineage reveals vascular patterning defects arising solely from the abnormal function of cells derived from the Foxd1 lineage. Using murine genetics and state-of-the art functional imaging techniques in collaboration with Dr. Peti-Peterdi, we will investigate the role of Pbx1 transcriptional regulation in the Foxd1 lineage.
In Aim 1, we will determine how conditional Pbx1 ablation perturbs renal hemodynamics.
Aim 2 will investigate the role of Pbx1-TR regulation in controlling the secretion of angiogenic factors by Foxd1-derivatives. Finally, in Aim 3 we will test whether Pbx1 transcriptional regulation in the mature kidney plays a role in its response to injury. Results of these studies investigating the mechanisms of gross renal vascular patterning will provide important clues for the design of protocols to functionally vascular renal tissues engineered in vitro and may inspire novel techniques to attenuate renal fibrosis, a major cause of end stage renal disease.
Development of the unique structure of the renal vascular bed remains poorly understood, despite its essential role in renal function. Here, we analyze renal vascular patterning in the developing and injured kidney. Results will provide invaluable clues for vascularizing renal replacement tissues engineer in vitro.
