Mediators of tubuloglomerular feedback regulation of glomerular filtration: ATP and adenosine

In the juxtaglomerular apparatus of the kidney the loop of Henle gets into close contact to its parent glomerulus. This anatomical link between the tubular system and the vasculature of the afferent and efferent arteriole enables specialized tubular cells, the macula densa (MD) cells, to establish an intra-nephron feedback loop designed to control preglomerular resistance and thereby single nephron glomerular filtration rate. This review focuses on the signalling mechanisms which link salt-sensing MD cells and the regulation of preglomerular resistance, a feedback loop known as tubuloglomerular feedback (TGF). Two purinergic molecules, ATP and adenosine, have emerged over the years as most likely candidates to serve as mediators of TGF. Data will be reviewed supporting a role of either ATP or adenosine as mediators of TGF. In addition, a concept will be discussed that integrates both ATP and adenosine into one signalling cascade that includes (i) release of ATP from MD cells upon increases in tubular salt concentration, (ii) extracellular degradation of ATP to form adenosine, and (iii) adenosine-mediated vasoconstriction of the afferent arteriole.