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 afferent arteriolar 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<unk>  and NKCC2 can be seen through the administration of loop diuretics like furosemide. Furosemide blocks NaCl reabsorption mediated by the NKCC2 at the ascending loop of henle, which leads to decreased renin release. Excluding loop diuretic use, the usual situation that causes a reduction in reabsorption of NaCl via the NCC2 at the macula densa (DCT) is a low tubular lumen concentration of NaCl due to low GFR. Reduced NaCl uptake via the NCC2 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: # 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. # 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. #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 both vasoconstriction and vasodilation, with perhaps the former in the lower range and the latter in the higher range of NaCl concentrations (2). When<unk>  regulation of afferent arteriolar tone is prevented by interrupting the<unk>  loop, and when the sensing mechanism is fully activated by saturating NaCl concentrations,<unk>  reduces GFR on average by approximately 45% and PGC by approximately 20%. Afferent arteriolar resistance increases by 50% or less, consistent with a radius reduction of approximately 10%, if Poiseuille's law holds. Thus,<unk> -induced vasoconstriction is usually limited in magnitude.
Tubuloglomerular feedback
Natural apophyseal glides
Retrograde perfusion
Renal urea handling
Renal sodium reabsorption
Reproductive compensation
Renal chloride reabsorption
Lymphatic pump