The long term objective of this research is to elucidate the cellular mechanisms that are responsible for the transmission of tubuloglomerular feedback signals. The feedback mechanism operates between the macula densa cells of the distal tubule and vascular elements and participates in the control of glomerular filtration rate. This area is important since alterations in feedback transmission process may play a role in hypertension and diabetes. Signal transmission will be investigated using, in vivo micropuncture studies in anesthetized rats, and in vitro studies using isolated perfused cortical thick ascending limb (CTAL) with attached glomeruli from rabbit kidney. Studies will focus on further defining the cellular mechanisms for signal transduction between macula densa cells, extraglomerular mesangial cells, and smooth muscle cells of the arterioles. Experiments will determine the role of adenosine receptors in activating macula densa cytosolic calcium concentration, the transduction of tubuloglomerular feedback signals and the constriction of the vascular elements. Other studies will continue to evaluate the regulation of volume flow and water permeability of the macula densa plaque. Electrophysiological studies will further elucidate specific transport pathways in macula densa cells. Coupled with direct measurements of macula densa intracellular sodium and chloride concentrations using fluorescent probes, these studies will allow us to gain significant insight into transport properties of macula densa cells. Continued measurements of macula densa intracellular pH and cytosolic calcium concentration will be performed to determine the role of cell pH and calcium in macula densa cell signaling. Also, we will develop an in vitro model of tubuloglomerular feedback by further assessing afferent arteriole and efferent arteriole cytosolic calcium concentration during changes in luminal fluid sodium chloride concentration. Finally, video analysis fluorescent microscopy will be used to evaluate communication between the various cellular components involved in the feedback pathway. These studies should provide new and important information concerning the tubuloglomerular feedback signal transmission process and allow greater insight into feedback-- mediated alterations in glomerular hemodynamics that may occur under pathophysiological conditions.
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