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.

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). 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 intitiates purinergic signaling. ATP can be released from cells through pannexin channels. Extracellular ATP is converted 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. 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:
 * atrial natriuretic peptide
 * nitric oxide
 * cAMP
 * PGI2
 * high-protein diet
 * adenosine
 * prostaglandin E2

Factors that increase TGF sensitivity include:
 * adenosine
 * 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. When added to any additional renal disease, this may cause permanent glomerular damage.