RBP-J Regulates the Identity and Plasticity of Renin Cells: a Fundamental Mechanism to Control Homeostasis
Castellanos Rivera, Ruth M., Department of Biology, University of Virginia
Gomez, Ariel, Department of Pediatrics, University of Virginia
Grainger, Robert, Department of Biology, University of Virginia
Renin is a hormone/enzyme crucial for maintaining blood pressure and fluid electrolyte homeostasis. In adult animals, renin-expressing cells are restricted to the afferent arterioles at the entrance to the glomeruli, and are referred to as juxtaglomeular (JG) cells. Homeostatic challenges such as dehydration or hypotension causes a dedifferentiation of vascular smooth muscle cells along the afferent arterioles to reacquire the renin cell phenotype. The exact mechanism underlying the identity and plasticity of renin cells remains unknown. This dissertation focuses on determining whether the canonical Notch signaling pathway, which is important for cell-cell communication and cell fate decisions, regulates the identity and plasticity of renin cells. We discovered that RBP-J, a central transcriptional regulator in Notch signaling maintains the number of renin-expressing cells and is crucial for vascular smooth muscle cells (VSMC) to reacquire the renin cell phenotype. In addition, a bacterial artificial chromosome transgenic reporter mouse showed that RBP-J regulates the transcriptional activity of renin directly via its promoter region. Furthermore, lineage studies in RBP-J conditional knockout mice (RBP-J cKO) tracing the progeny of renin precursor cells revealed that renin lineage cells remain in the kidney, suggesting that these cells undergo a change in phenotype. We discovered that RBP-J has a dual function in JG cells: acting as an activator to maintain the expression of genes important for both the endocrine and contractile phenotype, and as a repressor to repress genes from other lineages. In addition, blockade of the - secretase complex, responsible for the maturation of the Notch receptor, mimics the phenotype found in RBP-J cKO mice, suggesting that the effect of RBP-J on renin cells is dependent on Notch signaling. We attempted to identify which of the Notch receptors is involved in the RBP-J cKO and -secretase inhibitor treated mice phenotype. We found that Notch 2 is the likely candidate involved in maintaining the identity of JG cells. Together, two major components of the canonical Notch signaling pathway, RBP-J and the -secretase complex, are crucial in the identity and plasticity of JG cells, and RBP-J is also important to maintain the identity of the renal VSMCs of the kidney.
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PHD (Doctor of Philosophy)
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