The long term objective of this proposal is to gain insight into the molecular mechanisms of angiotensin II (All) action and their role in modulation of renal function. The complexity of the renin - angiotensin system has become more apparent in recent years as the multiplicity of receptor signaling cascades, and biological responses has emerged. This laboratory has made important contribution to our understanding of receptor classification, regulation, and function and proposes to continue this line of investigation. New observations suggest that All binds to multiple G- protein coupled receptor subtypes within the kidney, one of which differs pharmacologically from previously reported sites. In addition, renal All receptors appear to be coupled to multiple G-proteins some of which are selectively increased in a model of All-induced hypertension. Thus, the aims of this proposal are designed to test the hypothesis that exaggerated renal responses to All in genetic and non-genetic models of hypertension are due at least in part to differential phenotypic expression of G- proteins coupled to All receptor subtypes thereby facilitating hypertensiongenic signal transduction pathways. To address this hypothesis we must first have more information on All receptor-subtype distribution and interaction with specific G-proteins in renal cell types participating in blood pressure regulation.
Aim 1 - To determine the pharmacological and molecular basis for the All receptor subtypes distribution within the kidney.
Aim 2 - To identify the GTP binding proteins mediating All- induced signal transduction by the receptor subtypes present in the kidney.
Aim 3 - To ascertain the extent to which All receptor subtypes and G- protein interactions contribute to enhanced signal transduction early in tahe development of hypertension. A strength of this proposal is the variety of """"""""state-of-the-art"""""""" techniques that will be employed to test this hypothesis in the areas of molecular biology, biochemistry and cell physiology. The studies will make an important contribution to our understanding of the vascular biology of the renin-angiotensin system.
| Huang, Chunfa; Miller, Richard Tyler (2010) Novel Ca receptor signaling pathways for control of renal ion transport. Curr Opin Nephrol Hypertens 19:106-12 |
| Yu, Changqing; Yang, Zhiwei; Ren, Hongmei et al. (2009) D3 dopamine receptor regulation of ETB receptors in renal proximal tubule cells from WKY and SHRs. Am J Hypertens 22:877-83 |
| Zeng, Chunyu; Asico, Laureano D; Yu, Changqing et al. (2008) Renal D3 dopamine receptor stimulation induces natriuresis by endothelin B receptor interactions. Kidney Int 74:750-9 |
| Zeng, Chunyu; Armando, Ines; Luo, Yingjin et al. (2008) Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice. Am J Physiol Heart Circ Physiol 294:H551-69 |
| Zeng, Chunyu; Villar, Van Anthony M; Eisner, Gilbert M et al. (2008) G protein-coupled receptor kinase 4: role in blood pressure regulation. Hypertension 51:1449-55 |
| Resnick, Andrew; Hopfer, Ulrich (2008) Mechanical stimulation of primary cilia. Front Biosci 13:1665-80 |
| Woost, Philip G; Kolb, Robert J; Chang, Chung-Ho et al. (2007) Development of an AT2-deficient proximal tubule cell line for transport studies. In Vitro Cell Dev Biol Anim 43:352-60 |
| Resnick, Andrew; Hopfer, Ulrich (2007) Force-response considerations in ciliary mechanosensation. Biophys J 93:1380-90 |
| Huang, Chunfa; Miller, R Tyler (2007) Regulation of renal ion transport by the calcium-sensing receptor: an update. Curr Opin Nephrol Hypertens 16:437-43 |
| Ulmasov, Barbara; Bruno, Jonathan; Woost, Philip G et al. (2007) Tissue and subcellular distribution of CLIC1. BMC Cell Biol 8:8 |
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