Tubuloglomerular feedback

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 mainly 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. Furosemide blocks NaCl reabsorption mediated by the NKCC2 at the macula densa, which leads to increased renin release. Excluding loop diuretic use, the usual situation that causes a reduction in reabsorption of NaCl via the NKCC2 at the macula densa is a low tubular lumen concentration of NaCl. Reduced NaCl uptake via the NKCC2 at the macula densa leads to increased renin release, which leads to restoration of plasma volume, and to dilation of the afferent arterioles, which leads to increased renal plasma flow and increased GFR.

The macula densa's detection of elevated sodium chloride concentration in the tubular lumen, which leads to a decrease in GFR, is based on the concept of purinergic signaling.

In response to increased flow of tubular fluid in the thick ascending limb/ increased sodium chloride (salt) concentration at the macula densa:

1. Elevated filtration at the glomerulus or reduced reabsorption of sodium and water by the Proximal Convoluted Tubule causes the tubular fluid at the macula densa to have a higher concentration of sodium chloride.
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. The ATP is subsequently converted to adenosine by ecto-5′-nucleotidase.
5. Adenosine constricts the afferent arteriole by binding with high affinity to the A₁ receptors a G_i/G_o, not to be confused with the α₁ receptor, which utilizes the G_q. Adenosine binds with much lower affinity to A_2A and A_2B receptors causing dilation of efferent arterioles.
6. The binding of adenosine to the A₁ receptor causes a complex signal cascade involving the G_i subunit deactivating Ac, thus reducing cAMP and the G_o subunit activating PLC, IP3 and DAG. The IP3 causes the release of intracellular calcium, which spreads to neighboring cells via gap junctions creating a "TGF calcium wave". This causes afferent arteriolar vasoconstriction, decreasing the glomerular filtrate rate.
7. The G_i and increased intracellular calcium, cause a decrease in cAMP which inhibits Renin release from the juxtaglomerular cells. 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.

In response to decreased flow of tubular fluid in the thick ascending limb / decreased salt concentration at the macula densa:

1. Reduced filtration at the glomerulus or increased reabsorption of sodium and water by the Proximal Convoluted Tubule causes fluid in the tubule at the macula densa to have a reduced concentration of sodium chloride (because there was more time for sodium chloride to be reabsorbed from that fluid in the thick ascending limb).
2. NKCC2 has a lower activity and subsequently causes a complicated signaling cascade involving the activation of: p38, (ERK½), (MAP) kinases, (COX-2) and microsomal prostaglandin E synthase (mPGES) in the macula densa.
3. This causes the synthesis and release of PGE2.
4. PGE2 acts on EP2 and EP4 receptors in juxtaglomerular cells and causes renin release.
5. Renin release activates RAAS leading to many outcomes including an 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:

Factors that increase TGF sensitivity include:

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