The kidney is a highly vascularized organ that in the normal adult receives about 20% of the cardiac output. The unique spatial arrangement of the kidney arterioles with each nephron is crucial for the regulation of renal blood flow, glomerular filtration rate and other specialized kidney functions that maintain homeostasis. Thus, the proper and timely assembly of the arterioles with their respective nephrons is a crucial morphogenetic event leading to the formation of a functioning kidney necessary for independent extrauterine life. The mechanisms that govern the development of the kidney vasculature are poorly understood.
Foxd1+ cells and their descendants, the Ren+ precursors, are the earliest metanephric progenitors for all the mural cells of the kidney arterioles including JG cells, pericytes, arteriolar smooth muscle cells (SMCs) and mesangial cells.
Proposed model for the formation of the renal arteriole from Foxd1+ progenitor cells. Black solid arrows indicate current knowledge. Blue dashed arrows indicate the hypotheses we propose to test. The renin cell precursor gives rise to a subset of vascular SMCs. (click image for enlarged view)[/caption]We recently showed that deletion of RBP-J (the final transcriptional effector for all Notch receptors) is required to maintain the number of renin-expressing cells, and that it is crucial in the plasticity of vascular SMCs to regain the renin phenotype in response to a threat to homeostasis. Preliminary lineage tracing studies in vivo also suggest that cells from the renin lineage harboring the RBP-J -/- mutation do not die, adopting instead a distinct myofibroblast phenotype. Those experiments suggest that RBP-J regulates the fate and maintenance of renin cells. We anticipate that similar mutation further upstream from the renin precursor, such as in the Foxd1+ progenitors, will significantly affect the differentiation of the cells that compose the renal arteriolar tree.Using in vivo lineage tracing, time- and cell-specific conditional deletion approaches, genome wide epigenetic and gene-expression profiling and cell identification with appropriate differentiation markers we will test the he overall hypothesis that RBP-J is necessary for the differentiation of Foxd1+ and Renin+ progenitor cells and the establishment of cell identity-specific epigenetic marks and gene-expression patterns that culminate with the emergence of the differentiated mural cells of the renal arterioles.
The overall hypothesis to be tested is that RBP-J is necessary for the differentiation of FOXd1+ and Renin+ progenitor cells and the establishment of cell identity-specific epigenetic marks and gene-expression patterns that culminate with the emergence of the differentiated mural cells of the renal arterioles
The proposed work will fill an important gap in our knowledge by defining the precise cellular origin and mechanisms whereby early and intermediate stromal precursors lead to the successful formation of the renal arterial tree, without which there is no functioning kidney. Elucidating how RBP-J regulates renal arterial development and mesangial cell differentiation is novel and could lead to a new understanding of vascular development and disease with eventual therapeutic applications. As designed, the proposed experiments will solve an existing challenge and generate new and exciting information of relevance to the fields of regeneration and vascular development and plasticity with the potential to benefit children and adults with kidney and vascular diseases.