The juxtaglomerular apparatus (JGA) is an anatomic structure in the mammalian kidney which links the glomerular vascular pole with the macular densa cells of the distal tubule. There is evidence that this structure is important for regulation of renin secretion and renal blood flow. Research is aimed at understanding the interactions between the cell types which make up the juxtaglomerular apparatus. Previous work has established that physiological increases in macula densa NaC1 concentration produce local preglomerular vasoconstriction and inhibition of renin secretion. The proposed studies focus on the role of EDRF or nitric oxide in signal transmission in the juxtaglomerular apparatus. Recent evidence has established that a constitutive, calcium-activated NO synthase is present in the macula densa or with the state of the animal, and that macula densa NO may act to influence renin secretion and/or glomerular vascular tone.
In specific aim 1, we propose to assess expression of the isoforms of NOS and the soluble guanylyl cyclases in the JGA at the mRNA and protein level. We propose to examine their cellular localization using in situ hybridization and immunohistochemical techniques and their regulation by salt balance using quantitative PCR.
In specific aims 2 and 3, we propose a series of functional studies on the effects of NO on renin and vascular tone.
In specific aim 4, we propose direct measurements of macula densa NO generation. Proposed studies use a combination of intact animal studies, isolated in vitro systems, and cell culture methods. The long term aim of these studies is to better define the basic cellular mechanisms that underlie local control of renin secretion, renin synthesis and glomerular vascular tone. We expect that the resultant insights will contribute to the understanding of disease states in which these regulatory events may be disordered, such as congestive heart failure, some forms of hypertension and progressive renal insufficiency.
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