Tubuloglomerular feedback

In the physiology of the kidney, tubuloglomerular feedback (TGF) is one of several mechanisms the kidney uses to regulate glomerular filtration rate (GFR). It involves the concept of purinergic signaling, in which an increased distal tubular sodium chloride concentration causes a basolateral release of ATP from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level.[1][2][3]

Background

Normal renal function requires that the flow through the nephron is kept within a narrow range. When tubular flow (that is, GFR) lies outside this range, the ability of the nephron to maintain solute and water balance is compromised. Additionally, changes in GFR may result from changes in renal blood flow (RBF), which itself must be maintained within narrow limits. Elevated RBF may damage the glomerulus, while diminished RBF may deprive the kidney of oxygen. Tubuloglomerular feedback provides a mechanism by which changes in GFR can be detected and rapidly corrected for on a minute-to-minute basis as well as over sustained periods.

Regulation of GFR requires both a mechanism of detecting an inappropriate GFR as well as an effector mechanism that corrects it. The macula densa serves as the detector, while the glomerulus acts as the effector. When the macula densa detects an elevated GFR, it releases several molecules that cause the glomerulus to rapidly decrease its filtration rate. (Technically, the macula densa detects a SNGFR, single nephron GFR, but GFR is used here for simplicity.)

Mechanism

The macula densa is a collection of densely packed epithelial cells at the junction of the thick ascending limb (TAL) and distal convoluted tubule (DCT). As the TAL ascends through the renal cortex, it encounters its own glomerulus, bringing the macula densa to rest at the angle between the afferent and efferent arterioles. The macula densa's position enables it to rapidly alter glomerular resistance in response to changes in the flow rate through the distal nephron.

The macula densa uses the composition of the tubular fluid as an indicator of GFR. A large sodium chloride concentration is indicative of an elevated GFR, while low sodium chloride concentration indicates a depressed GFR. Sodium chloride is sensed by the macula densa by an apical Na-K-2Cl cotransporter (NKCC2). A decrease in sodium chloride levels triggers the release of signaling molecules from the macula densa, causing an increase in GFR. This increase is thought to be mediated largely by the relative levels of vasoconstriction in the afferent & efferent arterioles.

The macula densa's detection of elevated sodium chloride, which leads to a decrease in GFR, is based on the concept of purinergic signaling.[1][2][4] ATP can be released from cells through pannexin channels. Extracellular ATP is converted to adenosine, which binds to adenosine A1 receptors on extraglomerular mesangial cells, triggering a rise in intracellular calcium levels. This calcium signal is then propagated via gap junctions to adjacent cells, including granular cells of the juxtaglomerular apparatus and vascular smooth muscle cells of the afferent arteriole, resulting in afferent arteriole vasoconstriction and a decrease in renin release.[5] Both of these changes tend to decrease GFR.

Modulation

There are several factors that may modulate the sensitivity of tubuloglomerular feedback. A decreased sensitivity results in higher tubular perfusion, while an increased sensitivity results in lower tubular perfusion.

Factors that decrease TGF sensitivity include:[6]

Factors that increase TGF sensitivity include:[6]

High-protein diet

The increased load on the kidney of high-protein diet is a result of an increase in reabsorption of NaCl. This causes a decrease in the sensitivity of tubuloglomerular feedback, which, in turn, results in an increased glomerular filtration rate. This increases pressure in glomerular capillaries.[6] When added to any additional renal disease, this may cause permanent glomerular damage.

References

  1. 1 2 Arulkumaran, Nishkantha; Turner, Clare M.; Sixma, Marije L.; Singer, Mervyn; Unwin, Robert; Tam, Frederick W. K. (1 January 2013). "Purinergic signaling in inflammatory renal disease". Frontiers in Physiology 4. doi:10.3389/fphys.2013.00194. PMC 3725473. PMID 23908631. Extracellular adenosine contributes to the regulation of GFR. Renal interstitial adenosine is mainly derived from dephosphorylation of released ATP, AMP, or cAMP by the enzyme ecto-5′-nucleotidase (CD73) (Le Hir and Kaissling, 1993). This enzyme catalyzes the dephosphorylation of 5′-AMP or 5′-IMP to adenosine or inosine, respectively, and is located primarily on the external membranes and mitochondria of proximal tubule cells, but not in distal tubule or collecting duct cells (Miller et al., 1978). ATP consumed in active transport by the macula densa also contributes to the formation of adenosine by 5- nucleotidase (Thomson et al., 2000). Extracellular adenosine activates A1 receptors on vascular afferent arteriolar smooth muscle cells, resulting in vasoconstriction and a reduction in GFR (Schnermann et al., 1990).
  2. 1 2 Praetorius, Helle A.; Leipziger, Jens (1 March 2010). "Intrarenal Purinergic Signaling in the Control of Renal Tubular Transport". Annual Review of Physiology 72 (1): 377–393. doi:10.1146/annurev-physiol-021909-135825. PMID 20148681.
  3. ↑ Persson, A. E. G.; Lai, En Yin; Gao, Xiang; Carlström, Mattias; Patzak, Andreas (1 January 2013). "Interactions between adenosine, angiotensin II and nitric oxide on the afferent arteriole influence sensitivity of the tubuloglomerular feedback". Frontiers in Physiology 4. doi:10.3389/fphys.2013.00187.
  4. ↑ Carlstrom, M.; Wilcox, C. S.; Welch, W. J. (2010). "Adenosine A2 receptors modulate tubuloglomerular feedback". AJP: Renal Physiology 299 (2): F412–F417. doi:10.1152/ajprenal.00211.2010. PMC 2928527. PMID 20519378.
  5. ↑ Vallon V (2003). "Tubuloglomerular feedback and the control of glomerular filtration rate". News Physiol. Sci. 18 (4): 169–74. PMID 12869618.
  6. 1 2 3 Walter F., PhD. Boron (2005). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.
  • Brenner & Rector's The Kidney (7th ed.). Saunders, An Imprint of Elsevier. 2004. 
  • Eaton, Douglas C., Pooler, John P. (2004). Vander's Renal Physiology (8th ed.). Lange Medical Books/McGraw-Hill. ISBN 0-07-135728-9. 
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