The juxtaglomerular apparatus (JGA), which displays a unique arrangement of tubule (macula densa; MD), vasculature (afferent and efferent arterioles; Af- and Ef-Art) and interstitial cells, is the site of tubuloglomerular feedback (TGF) and renin release. Both TGF and the renin-angiotensin system are important for fluid volume and electrolyte homeostasis and consequently regulation of blood pressure. Alteration of TGF has been reported in many physiological and pathological conditions, such as hypertension, uninephrectomy, high protein intake and hyperglycemia. Studies have shown that the Af-Art is an important site of both TCF response and renin release. However, attempts to study MD-mediated changes in both Af-Art tone and renin release directly and simultaneously have been hindered by the anatomical complexity of the JCA, and we do not fully understand the mechanism of signal transmission responsible for either TGF or renin release. We have recently developed an in vitro preparation in which a single microdissected rabbit Af -Art with its glomerulus is microperfused with and without simultaneous perfusion of the attached MD. We have observed that increasing the NaCl concentration of the MD perfusate (without correcting osmolality) constricts the Af -Art at the vascular pole, and found it feasible to measure renin release from a single microperfused Af -Art. This preparation has the advantage of allowing us to observe the Af -Art directly while controlling the perfusion pressure without systemic hemodynamic and hormonal influences. Using this novel preparation, we propose to test the hypothesis that 1) both the pressure in the Af-Art and NaCl concentration (and osmolality) at the MD control Af-Art tone and renin release, with significant interaction between them; 2) the renin-angiotensin system, adenosine and endothelium-derived relaxing factors modify MD-mediated changes in both Af-Art tone and renin release; 3) heterogeneity of MD-mediated changes in Af-Art tone exists between superficial and deeper nephrons. The diameter of the Af-Art and renin release will be measured while varying the NaCl concentration at the MD and/or the pressure in the Af-Art. To monitor the perfusion pressure of the Af -Art, we will insert a pressure-measuring pipette through the perfusion pipette into the Af-Art. The new information obtained will greatly aid our understanding of the mechanism by which the JGA controls both glomerular hemodynamics and renin release and the alterations seen in many pathophysiological conditions.
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