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 adenosine 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 mainly by the macula densa by an apical Na-K-2Cl cotransporter (NKCC2). The relationship between the TGF and NKCC2 can be seen through the administration of loop diuretics like furosemide.[4] An increase in sodium chloride levels, caused by furosemide's inhibition of NKCC, triggers the release of signaling molecules from the macula densa that down-regulate release of renin and an thus decrease in GFR.

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][5]

In response to increased salt levels:

  1. Excessive filtration at the glomerulus or inadequate sodium uptake by the Proximal Convoluted Tubule/Thick Ascending Loop, causes fluid in the distal convoluted tubule to have an abnormally high concentration of sodium.
  2. Apical Na-K-2Cl cotransporters (NKCC2), which are found on the surface of the macula densa cells, are exposed to the fluid with a higher sodium concentration, and as a result more sodium is transported into the cells.
  3. The macula densa cells do not have enough Na/K ATPases on their basolateral surface to excrete this added sodium. This results in an increase of the cell's osmolarity.
  4. Water flows into the cell along the osmotic gradient, causing the cell to swell. When the cell swells, ATP escapes though a basolateral, stretch-activated, non-selective Maxi-Anion channel.[6] The ATP is subsequently converted to adenosine by ecto-5′-nucleotidase.[7]
  5. Adenosine constricts the afferent arteriole by binding with high affinity to the A1 receptors[8][9] a Gi/Go, not to be confused with the α1 receptor, which utilizes the Gq. Adenosine binds with much lower affinity to A2A and A2B[10] receptors causing dilation of efferent arterioles.[9]
  6. The binding of adenosine to the A1 receptor causes a complex signal cascade involving the Gi subunit deactivating Ac, thus reducing cAMP and the Go subunit activating PLC, IP3 and DAG.[11] The IP3 causes the release of intracellular calcium, which spreads to neighboring cells via gap junctions creating a "TGF calcium wave".[7] This causes afferent arteriolar vasoconstriction, decreasing the glomerular filtrate rate.
  7. The Gi and increased intracellular calcium, cause a decrease in cAMP which inhibits Renin release from the juxtaglomerular cells.[11] In addition, when macula densa cells detect higher concentrations of Na and Cl, they inhibit nitric oxide synthetase (decreasing renin release), but the most important inhibitory mechanism of renin synthesis and release is elevations in juxtaglomerular cell calcium concentration.[4]

In response to decreased salt levels:

  1. Reduced filtration at the glomerulus causes fluid in the distal convoluted tubule to have an abnormally low concentration of sodium.
  2. NKCC2 has a lower activityand subsequently causes complicates signaling cascade involving the activation of: p38, (ERK½), (MAP) kinases, (COX-2) and microsomal prostaglandin E synthase (mPGES) in the macula densa.[4]
  3. This causes the synthesis and release of PGE2.
  4. PGE2 acts on EP2 and EP4 receptors in juxtaglomerular cells and causes renin release.[4]
  5. Renin release activates RAAS leading to many outcomes including and increased 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:[12]

Factors that increase TGF sensitivity include:[12]

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.[12] When added to any additional renal disease, this may cause permanent glomerular damage.

See also

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. 1 2 3 4 Peti-Peterdi, János; Harris, Raymond C. (2010). "Macula densa sensing and signaling mechanisms of renin release.". Journal of the American Society of Nephrology. doi:10.1681/ASN.2009070759. PMC 4577295. PMID 20360309.
  5. ↑ 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.
  6. ↑ Komlosi, Peter; Peti-Peterdi, Janos; Fuson, Amanda; Fintha, Attila; Rosivall, Laszlo; Darwin Bell, Phillip (2004). "Macula densa basolateral ATP release is regulated by luminal [NaCl] and dietary salt intake.". American Journal of Physiology - Renal Physiology 286. doi:10.1152/ajprenal.00336.2003. PMID 14749255.
  7. 1 2 Burnstock, Geoffrey; Evans, Louise C.; Bailey, Matthew A. (2014). "Purinergic signalling in the kidney in health and disease.". The Official Journal of the International Purine Club 10, (1,): 71–101. doi:10.1007/s11302-013-9400-5. PMC 3944043.
  8. ↑ W S Spielman, L J Arend, "Adenosine receptors and signaling in the kidney.", American Heart Association, 1991
  9. 1 2 Vallon, Volker; Osswald, Hartmut (2009). "Adenosine receptors and the kidney". Handbook of Experimental Pharmacology 193: 443–470. PMID 19639291.
  10. ↑ Feng, MG; Navar, LG (2010). "Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation.". American journal of physiology. Renal Physiology. PMID 20462966.
  11. 1 2 Ortiz-Capisano, M. Cecilia; Atchison, Douglas K; Harding, Pamela; Lasley, Robert D.; Beierwaltes, William H. (2013). "Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway". American journal of physiology. Renal Physiology. doi:10.1152/ajprenal.00710.2012. PMC 3798729. PMID 23884142.
  12. 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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