Mechanism for Antagonistic Signal Transduction Pathways in ren-1 Regulation in Kidney

University Of Massachusetts Medical School, Worcester MA

Investigators

Abstract

Blood pressure regulation, salt and water balance, and nervous system control are significantly influenced by the kidney. A hormonal renin (ren-1)-angiotensin system in the kidney is critical for appropriate regulation, balance, and control. Ren-1 is upregulated conventionally by a cyclic-AMP signal transduction pathway, although the signaling intermediates have not been discovered on account of impoverished technology. Paradoxically, ren-1 is downregulated unconventionally by a calcium signal transduction pathway, but again the signaling intermediates have not been discovered. The objective of this project is to discover and describe the signaling intermediates in the calcium-mediated downregulation of ren-1 gene expression, using kidneys and ren-1-producing cells under different stresses to alter the calcium signal transduction pathway. The approaches are to scan kidneys and ren-1-producing cells using microarray technology, and to use proteomic tools to discover the cluster of genes associated with the calcium-signal transduction pathway. This project will simultaneously screen 2,400 arbitrarily chosen but verified transcripts against mRNAs from isolated perfused kidneys and ren-1-producing cells in culture to define a cluster of genes most consistently associated with ren-1 expression. This cluster will be used to test the hypothesis that ren-1 downregulation is associated with increased expression of not just 2 signaling intermediates as currently believed, but with at least 14 other intermediates. These observations will be important not only because it is the first time the intermediates of an antagonistic signal transduction system has been measured and described, but also because it may clarify the paradoxical molecular nature of calcium and ren-1 in blood pressure regulation and salt and water balance.