MECHANISMS OF TUBULOGLOMERULAR FEEDBACK

The available evidence suggests that the macula densa, located at the end of the thick ascending limb, senses tubular flow based on the concentrations of sodium and chloride in the local filtrate. The sensing apparatus appears to be apical Na⁺/K⁺/2Cl⁻ (NKCC2) cotransporters. When tubular flow rates are high, there is a slight decrease in solute reabsorption before the macula densa, and thus higher concentrations of sodium and chloride are present at this area. Increased activation of NKCC2 transporters ensues, which leads to constriction of the afferent arteriole and inhibition of renin release. In contrast, when tubular flow rates are low, decreased activation of NKCC2 transporters leads to dilation of the afferent arteriole and activation of renin release.

The exact signals that connect the NKCC2 transporters of the macula densa to the afferent and efferent arterioles remain poorly understood; however, there is increasing evidence that adenosine plays a key role. In one proposed model, increased reabsorption by NKCC2 transporters stimulates basolateral Na⁺/K⁺ ATPases. The increased ATP consumption yields ADP and AMP, which local proteins convert into adenosine. Adenosine, in turn, activates receptors on the surface of nearby extraglomerular mesangial cells, causing an increase in intracellular calcium levels. A wave of intracellular calcium is transmitted across gap junctions to the smooth muscle and granular cells of the afferent and efferent arterioles, causing constriction of the afferent arteriole and inhibition of renin release. In contrast, when there is low tubular flow and diminished reabsorption by NKCC2 transporters, the adenosine signal is eliminated, leading to dilation of the afferent arteriole and stimulation of renin release.

In addition, there is some evidence that macula densa cells contain COX-2 enzymes that are also stimulated when there is diminished reabsorption by NKCC2 transporters; these appear to synthesize prostaglandins that stimulate dilation of the afferent arteriole and promote renin release.