The juxtaglomerular apparatus (JGA) of the mammalian nephron is a structure which connects the distal tubule with the glomerular vascular pole. It is located at a nephron site where NaCI concentration varies considerably depending upon body salt balance. Previous studies in the applicant's laboratory have established that variations in tubular salt content are sensed, and signals are transmitted to the afferent arteriolar smooth muscle cells and renin-producing granular cells. The result of this information flow is regulation of glomerular vascular tone and renin secretion. The present application combines gene expression studies and functional studies, largely in transgenic animals, in order to clarify the molecular pathways critical for these responses. The first specific aim is to develop and apply methods that are suitable for studying regulation of GFR, blood flow and renin release in the mouse kidney at both the single nephron and organ level, in order to lay the foundation for later studies in genetically modified animals.
The second aim i s to study the effect of disruption in the regulation of angiotensin and of macula densa-derived nitric oxide on set point and sensitivity of the local vascular regulatory mechanisms, using mice with null mutations in ncNOS and AT1a receptors.
The third aim i s to evaluate the interactions between adenosine and arachidonic acid metabolities in local regulation in the JGA. The fourth specific aim is to evaluate the role of gene products which show high levels of expression in the JGA, but currently have no recognized regulatory role. Proteins whose possible contribution to JGA function is to be examined are the oxytocin receptor, PTH-related protein, and B6-integrin. The long term goal of these studies is to understand the cellular events responsible for local control of renin secretion and glomerular vascular tone, functions that are of central importance for the control of body fluid volume and arterial blood pressure.
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