In normal adult kidney the primary site of renin expression is the juxtaglomerular cell and renin expression there is associated with regulation of blood pressure and electrolyte balance. During renal organogenesis abundant renin expression is found transiently in association with the developing renal arterial system, and genetic or pharmacological disruption of renin-angiotensin system (RAS) signaling is associated with malformations of the vasculature. To study the mechanisms of transcriptional regulation governing the expression pattern of the renin gene, a renin-expressing cell line (As4.1) has been produced by transgene- targeted tumorigenesis, and is being used in transient transfection assays to define the c/s-acting sites in the promoter that are required for expression. Transgenic reporter lines expressing green fluorescent protein (GFP) under control of the renin promoter have been developed and are being used to verify the functionality of the identified sites in vivo. The GFP reporter lines are also being used to purify native renin-expressing cells from kidneys at different stages of renal ontogeny by FACS for expression-profiling utlizing the Affymetrix and MPSS platforms. The profiling studies have allowed identification of specific members of transcription factor families that constitute the frans-acting factors interacting at c/s regulatory sites in the renin promoter, and have implicated renin as the immediate downstream target of Notch regulation. The profiling has also permitted identification of a spectrum of other genes whose products specifically co-enrich with renin in the isolated cells. The pattern of expression suggests that the renin-expressing cell of early renal development corresponds to an activated vascular pericyte which is instructively engaged in communicating with endothelial and other cells to effect development of the arterial vasculature. Pericytes are mural cells that exhibit considerable developmental plasticity and are recognized to play an important role in angiogenesis, smooth muscle differentiation, and vascular remodeling. Their dysregulation has been implicated in diabetic microangiopathies, hypertension and inappropriate calcification of vascular tissue.
Under Aims 1 and 2, a prioritized plan to complete delineation and in vivo verification of major c/s and frans- acting components of renin promoter regulation through development is proposed.
Under Aim 3 a set of transgenic reporter strains will be developed and analyzed which will permit lineage tracing of the renin- expressing cell and expression-profiling of renin-expressing cells or their descendents at various stages during normal development and in response to pathophysiological perturbations. These studies will permit assessment of how changes in the transcription factor repertoire correlate with changes in renin expression.
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