Advertisement
Adenosine and ATP: traffic regulators in the kidney
Wilhelm Kriz
Department of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany.
Address correspondence to: Wilhelm Kriz, Department of Anatomy and Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany. Phone: 49-6221-54-8680; Fax: 49-6221-54-4951; E-mail: wilhelm.kriz@urz.uni-heidelberg.de.
Find articles by Kriz, W. in: JCI | PubMed | Google Scholar
First published September 1, 2004 - More info
J Clin Invest. 2004;114(5):611–613. https://doi.org/10.1172/JCI22669.
© 2004 The American Society for Clinical Investigation
Each human kidney is composed of one million nephrons, each of which is an individual unit that functions in large part independently of the others (Figure 1). The glomerulus, where filtration of the blood occurs, is a vascular and epithelial structure whose function is highly regulated. Although a variety of local and systemic hormones contribute significantly to this regulation, the anatomy of the nephron suggests an additional mode of control. The distal tubule, when it emerges from the medulla, is adherent to the glomerulus at the point of the macula densa. Ever since the anatomy of the whole mammalian nephron was discovered, this connection has suggested that the glomerulus likely receives signals from the tubules that transport the filtered fluid, not just from systemic hormones.
Figure 1Structural organization of the nephron. Blood vessels are shown in red; the glomerulus and the tubular system in gray. The afferent arteriole feeds the glomerular capillary network, where filtration of the blood occurs. The glomerular filtrate is processed as it travels through the different tubular segments. At the cell plaque of the MD, with which the TAL touches the vascular pole of its glomerulus, tubular fluid composition is sensed and paracrine signals are conveyed to smooth muscle and renin-producing cells of the afferent arteriole.
The conglomerate of cells at the site of contact is called the juxtaglomerular apparatus (JGA), and it is a cytoarchitectural feature of all mammalian kidneys (Figure 2). The JGA consists of, first, a plaque of tubular cells, the so-called macula densa (MD), that is located within the end portion of the thick ascending limb (TAL) of the loop of Henle, mediating contact between the TAL and the vascular pole of its parent glomerulus. It consists of, second, the extraglomerular mesangium, which is composed of cells and matrix and fills the angle between the afferent and efferent glomerular arterioles and, third, the VSMCs at the vascular pole, including the renin-producing juxtaglomerular granular cells. This intimate and systematic juxtaposition of tubular epithelial cells and vascular cells within the same nephron has given rise to early speculations about a functional connection in which a signal related to the composition of the tubular fluid at the MD affects glomerular vascular tone and glomerular filtration rate (1). It has now become clear that the JGA serves two different functions: it regulates the flow resistance of afferent arterioles in the so-called tubuloglomerular feedback mechanism, and it participates in the control of renin synthesis and release from the granular cells in the afferent arteriole (2). Researchers originally assumed that the two responses might be related to each other in that renin released from the granular cells not only has systemic relevance, but locally triggers the formation of Ang II and thus is responsible for the afferent vasoconstriction as well; however, it now appears that the final activation of smooth muscle and granular effector cells occurs through largely independent pathways. Renin release from granular cells is the major source of systemic Ang II and thus plays an essential role in controlling extracellular volume and blood pressure, whereas the vasoconstriction of the afferent arteriole locally serves to modulate the filtration of the concerned nephron. For both mechanisms, it is well established that a change in NaCl concentration in the tubular fluid at the MD causes a graded release of mediators that reach their target by diffusion, thus acting in a paracrine fashion. It is worth remembering that the extraglomerular mesangium that mediates contact between the MD and the effector cells is not vascularized, so that the buildup of any paracrine agent would not be perturbed by blood flow.
Figure 2Schematic showing the structural and functional relationships within the JGA. The MD cells are shown in brown, the extraglomerular mesangium in blue, the VSMCs in magenta, the renin-producing cells in green, the fibroblasts of the adjacent interstitium in yellow, and the blood vessels in red. Note that both signaling pathways from the MD pass the extraglomerular mesangium, either to reach the VSMCs (I) to regulate filtration or the renin-producing cells (II) to mediate renin secretion.
With respect to renin release, the most likely paracrine mediators of this process are prostaglandin E2 and nitric oxide (3–5), whereas the strongest experimental evidence for the vasoconstrictor response favors the notion that purinergic mediators, either ATP or adenosine, are responsible for signal transduction. A study by Castrop et al. reported in this issue of the JCI addresses the question of a possible interaction between ATP and adenosine in eliciting MD-dependent vasoconstriction (6).
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)