Tubuloglomerular Feedback ‐ A System For Nephron Self‐Regulation

Abstract

The large amounts of filtered NaCl represent a latent threat to body salt homeostasis by potentially overwhelming the tubular reabsorptive capacity. Tubuloglomerular feedback (TGF) is an autonomous, single nephron-based mechanism designed to contain this risk by regulating salt delivery into the collecting duct system where the transport capacity for NaCl is intrinsically limited. Deviations of NaCl concentration at the macula densa (MD) cells, whether caused by changes of GFR or proximal reabsorption, are translated into changes of afferent arteriolar resistance and inverse changes of GFR, thus preventing inappropriate late nephron overloading. The regulatory process in the juxtaglomerular control region begins with a change in NaCl uptake by MD cells that is mediated by the furosemide-sensitive Na,K,2Cl-cotransporter. Changes in NaCl transport then initiate events that lead to the release of ATP and to the generation of adenosine by a cascade of ecto-ATPases and ectonucleotidases. Afferent arteriolar vasomotor responses are mostly the result of activation of A1 adenosine receptors. The TGF response magnitude is variable with increases in sensitivity resulting mainly from high ambient angiotensin II levels, and decreases of sensitivity caused by nitric oxide generated locally by macula densa bNOS. TGF as a minute-to-minute stabilizer of distal salt delivery is critical in determining NaCl excretion during fast and random perturbations of filtration forces that are unrelated to body salt balance. Because renin secretion is partly under the control of NaCl at the MD, stability of distal NaCl concentration has the secondary consequence of supporting stability of plasma renin activity. Changes of TGF sensitivity secure the regulatory capacity of nephron self-regulation during prolonged alterations of MD NaCl that exceed the ambient regulatory range.