Ions and signal transduction in the macula densa.

Abstract

The body’s internal environment is regulated, in large part, by processes occurring in the juxtaglomerular apparatus (JGA) of nephrons. One such processes is the well described phenomenon of tubuloglomerular feedback (TGF). A second and related process, the control of renin secretion by the macula densa, is the subject of the report by Cheng et al. (1) in the present issue of the JCI. Because TGF and the macula densa control of renin are intertwined, this research also bears on events in the JGA beyond its role in the systemic renin-angiotensin-aldosterone system (RAAS), which itself has profound effects on salt excretion. Products of the RAAS formed downstream from renin act to conserve salt by causing glomerular vasoconstriction and by increasing reabsorption of salt and water from the proximal and distal nephrons. TGF allows changes in the chloride content of tubular fluid passing the macula densa at the end of Henle’s loop to effect a reciprocal change in single nephron glomerular filtration rate (SNGFR). This negative feedback mechanism operates on a time scale of seconds and stabilizes both SNGFR and the rate at which salt reaches the distal nephron. In addition to initiating the TGF response, chloride also exerts an effect over longer times on renin secretion, the rate-limiting event in the RAAS. Specifically, when the apical macula densa is exposed to high chloride concentrations for 20 minutes or more, renin secretion from granular cells in the nearby afferent arteriole is suppressed (2). As a consequence, production of the peptide angiotensin II declines, as does the rate of salt and water reabsorption from the proximal tubule. The subsequent increase in late peroximal flow leads directly to an increase in chloride concentration at the macula densa (a consequence of the kinetics of salt transport in the water-impermeable ascending loop of Henle). Therefore, suppression of RAAS activity at the nephron level will increase both late proximal flow and macula densa chloride.