the fluid with a higher sodium concentration, and as a result more sodium is transported into the cells. 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. Water flows into the cell along the osmotic gradient, causing the cell to swell. When the cell swells, ATP escapes through a basolateral, stretch-activated, non-selective Maxi-Anion channel. The ATP is subsequently converted to adenosine by ecto-5′-nucleotidase. Adenosine constricts the afferent arteriole by binding with high affinity to the A1 receptors a Gi/Go. Adenosine binds with much lower affinity to A2A and A2B receptors causing dilation of efferent arterioles. 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. The IP3 causes the release of intracellular calcium, which spreads to neighbouring cells via gap junctions creating a "TGF calcium wave". This causes afferent arteriolar vasoconstriction, decreasing the glomerular filtrate rate. The Gi 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: 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. 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. This causes the synthesis and release of PGE2. PGE2 acts on EP2 and EP4 receptors in juxtaglomerular cells and causes renin release. Renin release activates RAAS leading to many outcomes including an increased GFR. The critical target of the trans-JGA signaling cascade is the glomerular afferent arteriole; its response consists of an increase in net vasoconstrictor tone resulting in reductions of glomerular capillary pressure (PGC) and glomerular plasma flow. Efferent arterioles appear to play a lesser role; experimental evidence supports