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). Changes in GFR are detected by the renal tubule, which sends feedback signals to the glomerulus, initiating a cascade of events that ultimately brings GFR to an appropriate level.

Additional recommended knowledge

How to quickly check pipettes?

Weighing the right way

What is the Correct Way to Check Repeatability in Balances?

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 in the distal convoluted tubule. As the loop of Henle 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. This places the macula densa in a unique position to rapidly alter glomerular resistance in response to changes in the flow rate through the distal nephron.

The distal renal tubule uses the composition of the tubular fluid as an indicator of GFR. A large amount of sodium chloride is indicative of an elevated GFR, while low sodium chloride indicates a depressed GFR. Sodium chloride is sensed by the macula densa by an apical Na-K-2Cl cotransporter (NKCC2). Detection of elevated sodium chloride levels triggers the release of signaling molecules from the macula densa, causing a drop in GFR. This drop is thought to be mediated largely by constriction of the afferent arteriole.

Precisely how the macula densa's detection of elevated sodium chloride leads to a decrease in GFR remains unknown. One proposed mechanism is that delivery of sodium chloride to the macula densa enhances the conversion of ATP to adenosine. Adenosine may then bind to adenosine A₁ receptors on extraglomerular mesangial cells, triggering a rise in intracellular calcium levels. This calcium signal may be 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.^[1]

Modulation

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

Factors that decrease TGF sensitivity include ^[2]:

• atrial natriuretic peptide
• nitric oxide
• cAMP
• PGI₂
• high protein diet

Factors that increase TGF sensitivity include:

• adenosine
• prostaglandin E2
• thromboxane
• HETE
• angiotensin II

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 the sensitivity of tubuloglomerular feedback, which, in turn, results in an increased glomerular filtration rate. This increases pressure in glomerular capillaries ^[3]. When added to any additional renal disease, this may cause permanent glomerular damage.

References

• (2004) Brenner & Rector's The Kidney, 7th ed., Saunders, An Imprint of Elsevier. 
• Eaton, Douglas C., Pooler, John P. (2004). Vander's Renal Physiology, 8th edition, Lange Medical Books/McGraw-Hill. ISBN 0-07-135728-9. 

1. ^ Vallon V (2003). "Tubuloglomerular feedback and the control of glomerular filtration rate". News Physiol. Sci. 18: 169-74. PMID 12869618.
2. ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.  for the examples atrial natriuretic peptide nitric oxide cAMP PGI₂ high protein diet adenosine prostaglandin E2 thromboxane 5-hydroxyeicosatetraenoic acid angiotensin II
3. ^ Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3.  Page 771