Release of renin by juxtaglomerular cells usually suffices to maintain blood pressure and fluid-electrolyte balance. However, if an adult mammal is subjected to manipulations that threaten homeostasis, smooth muscle cells along the renal arterioles undergo a remarkable transformation: they switch from a contractile to an endocrine phenotype acquiring the capacity to synthesize and release renin. Once homeostasis is reestablished, the transformed cells become smooth muscle cells again. The ability to switch on and off the renin phenotype seems to depend on the developmental history of the transformed cells: smooth muscle cells descend from renin precursors and may retain the memory to synthesize renin when necessary to regain homeostasis. Where in the genome the memory of the renin phenotype resides, how it is constructed, and how it is retained or erased as the cells differentiate or change physiological status is unknown. We observed that renin cells possess super-enhancers (SEs), dynamic clusters of large genomic regulatory regions that are strong candidates to regulate the reenactment of the renin phenotype. Our overall hypothesis is that the molecular memory of the renin phenotype resides in the chromatin state of the arteriolar cells and is mediated by a distinctive set of SEs that control the identity of renin cells and their descendants. Using in vivo and in vitro lineage tracking, reporters of gene activity, epigenome editing and chromatin imaging techniques, we propose to pursue the following interrelated hypotheses and aims:
Aim 1. Test the hypothesis that acquisition of the renin cell phenotype is accompanied by the establishment of unique SEs that enforce the expression of genes from the renin lineage.
Aim 2. Test the hypothesis that the renin SE regulates expression of the renin gene and through dynamic chromatin interactions with other genes controls renin cell identity. Understanding how vascular cells adopt and switch their identity is a fundamental biological question with applicability to multiple, renal and extra renal diseases. This knowledge may lead to novel targets to prevent renin cell fate changes that result in threatening cardiovascular, renal and hematopoietic diseases and inability to coordinate multiple homeostatic responses. By providing essential new knowledge regarding the mechanisms whereby arteriolar cells acquire and maintain their plasticity, a frontier basically unexplored, this proposal has the potential to benefit children and adults with kidney and vascular diseases and hypertension.
Understanding the mechanisms that control the identity, plasticity and fate of renin cells is of fundamental biological and medical importance. Such knowledge may lead to new strategies to preserve normal kidney and vascular structure and function.
| Sequeira-Lopez, Maria Luisa S; Gomez, R Ariel (2018) Preserving kidney health during intensive blood pressure control. Nat Rev Nephrol 14:537-538 |
| Mohamed, Tahagod; Sequeira-Lopez, Maria Luisa S (2018) Development of the renal vasculature. Semin Cell Dev Biol : |
