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Key Words kidney, tubuloglomerular feedback, renal hemodynamics, cell-to-cell, communication
Abstract Macula densa cells are renal sensor elements that detect changes in distal tubular fluid composition and transmit signals to the glomerular vascular elements. This tubuloglomerular feedback mechanism plays an important role in regulating glomerular filtration rate and blood flow. Macula densa cells detect changes in luminal sodium chloride concentration through a complex series of ion transport-related intracellular events. NaCI entry via a Na:K:2C1 cotransporter and Cl exit through a basolateral channel lead to cell depolarization and increases in cytosolic calcium. Na/H exchange (NHE2) results in cell alkalization, whereas intracellular [Na] is regulated by an apically located H(Na)-K ATPase and not by the traditional basolateral Na:K ATPase. Communication from macula densa cells to the glomerular vascular elements involves ATP release across the macula densa basolateral membrane through a maxianion channel. The adaptation of multi-photon microscopy is providing new insights into macula densa-glomerular signaling.
INTRODUCTION
Within the kidney, the juxtaglomerular apparatus (JGA) is the site for the formation and regulation of glomerular filtration. This hemodynamic-filtration unit is morphologically complex (Figure 1, see color insert), consisting of a hemodynamic conduit that includes the terminal segment of the afferent arteriole, the glomerular capillary network, and efferent arteriole. Glomerular capillaries, which are surrounded by Bowman's capsule, are also structurally and functionally connected with mesangial cells. In normal adult humans, filtration through this capillary network occurs at a rate of 180 liters a day, and this filtrate is modified and processed by passage through specialized tubular segments into final urine. A unique feature of each nephro-vascular unit is that near the terminal portion of the nephron, the tubule returns to and is closely associated with the JGA. At this site, the morphologically distinct tubular cells, called macula densa cells, face the JGA. These cells monitor tubular fluid flow and composition and send signals that regulate renal hemodynamics and the rate of filtration; this process has been termed tubuloglomerular feedback (TGF) (1-4).
Macula densa cells reside within the cortical thick ascending limb (cTAL), and it is this segment that is water impermeable and possesses the apically located, loop diuretic-sensitive, Na:K:2C1 cotransporter. The cTAL is responsible for the dilution of tubular fluid. Upon reaching the macula densa segment, reabsorption of NaCI...