The juxtaglomerular apparatus (JGA) is comprised of three types of specialized cells, epithelial cells of the distal tubule known as the macula densa (MD), extraglomerular mesangial cells, and renin-containing granular cells of the afferent arteriole. Physiological alterations in NaCl transport by the MD lead to an inverse change in renin secretion and a direct change in afferent arteriole tone; however, the signaling systems linking transport to these functional responses of the vasculature are not understood. Nitric oxide (NO), a ubiquitous vasodilator, is one candidate paracrine mediator of JGA function; renal expression of one isoform of NO synthase, the neuronal, constitutive form (ncNOS) is localized to the MD. The main objective of the proposed studies is to evaluate definitively the role of MD NO in signal transmission within the JGA by utilizing ncNOS deficient mice. In order to exploit the increasing availability of genetically modified mice such as this strain, improved methods for assessment of integrated function in mice are needed. The first specific aim of this project is to develop methods to permit studies of JGA function in the mouse.
In specific aim two we will assess the effect of deficiency in ncNOS on NaCl-dependent renin secretion.
Specific aim three is to evaluate the role of MD NO in local vascular effects; we propose to compare autoregulation of renal blood flow in wild-type and ncNOS(-) mice using frequency domain analysis to determine if either the myogenic or tubuloglomerular feedback responses are dependent on MD-generated NO. The long term goal of these studies is to identify and understand the signaling pathways of the JGA which are involved in regulating renin secretion and arteriole tone, functions which are of primary importance for controlling body fluid volume and arterial pressure.
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