An increase in the delivery of NaCl to the macula densa triggers vasoconstriction of the afferent arteriole of the same nephron. This is known as tubuloglomerular feedback. When the glomerular filtration rate (GFR) rises, the concentration of NaCl in the tubule fluid at the macula densa also increases. Consequently, there is an enhanced uptake of NaCl across the apical cell membrane of macula densa cells through the NKCC2 symporter. This leads to an increase in ATP and adenosine release, resulting in an elevation of intracellular calcium (Ca++) levels. ATP binds to P2X receptors and adenosine binds to adenosine A1 receptors on the plasma membrane of smooth muscle cells surrounding the afferent arteriole. Both of these interactions further increase intracellular Ca++, leading to vasoconstriction of the afferent arteriole and the restoration of GFR to normal levels. It is important to note that ATP and adenosine also inhibit renin release by granular cells in the afferent arteriole through the increase in intracellular Ca++ levels. This inhibition is a result of the electrical coupling between the granular and vascular smooth muscle cells. On the other hand, when GFR is reduced, the concentration of NaCl in the tubule fluid decreases, leading to a decrease in NaCl uptake into macula densa cells. Consequently, the release of ATP and adenosine by the macula densa decreases, resulting in a decrease in intracellular Ca++ levels in smooth muscle cells. This leads to an increase in GFR and stimulates renin release by granular cells. Additionally, the decrease in NaCl entry into macula densa cells enhances the production of PGE2, which also stimulates renin secretion by granular cells. Renin increases the plasma concentration of angiotensin II, a hormone that promotes NaCl and water retention by the kidneys.

Despite autoregulation, renal blood flow (RBF) and GFR can undergo slight changes as arterial blood pressure varies. Furthermore, several hormones and alterations in sympathetic nerve activity can modify RBF and GFR in response to changes in the extracellular fluid volume (ECFV). The myogenic mechanism and tubuloglomerular feedback are crucial in maintaining constant RBF and GFR when blood pressure is above 90 mm Hg and ECFV is within the normal range. However, when ECFV changes, various hormones, including sympathetic nerves, angiotensin II, prostaglandins, nitric oxide, endothelin, bradykinin, ATP, and adenosine, exert significant control over RBF and GFR. Figure 33.21 illustrates how changes in resistance of the efferent and afferent arterioles, mediated by the aforementioned hormones, modulate both RBF and GFR. The sympathetic neurons innervate the afferent and efferent arterioles, but their influence is minimal under normal ECFV conditions. However, when ECFV decreases, sympathetic nerves release norepinephrine and dopamine, while the adrenal medulla secretes circulating epinephrine. Norepinephrine and epinephrine cause vasoconstriction.
• Fig. 33.20 Cellular mechanism whereby an increase in delivery of NaCl to the macula densa causes vasoconstriction of the afferent arteriole of the same nephron (i.e., tubuloglomerular feedback). An increase in GFR elevates [NaCl] in tubule fluid at the macula densa. This in turn enhances uptake of NaCl across the apical cell membrane of macula densa cells via the 1Na+-1K+-2Cl− (NKCC2) symporter, which leads to an increase in [ATP] and [adenosine] (ADO) release. ATP binds to P2X receptors and adenosine binds to adenosine A1 receptors in the plasma membrane of smooth muscle cells surrounding the afferent arteriole, both of which increase intracellular [Ca++]. The rise in [Ca++] induces vasoconstriction of the afferent arteriole, thereby returning GFR to normal levels. Note that ATP and adenosine also inhibit renin release by granular cells in the afferent arteriole. This too results from an increase in intracellular [Ca++] as a reflection of electrical coupling of the granular and vascular smooth muscle (VSM) cells. When GFR is reduced, [NaCl] in tubule fluid falls, as does uptake of NaCl into macula densa cells. This in turn decreases release of ATP and adenosine by the macula densa, which decreases intracellular [Ca++] in smooth muscle cells and thereby increases GFR and stimulates renin release by granular cells. In addition a decrease in entry of NaCl into macula densa cells enhances production of PGE2, which also stimulates renin secretion by granular cells. As discussed in detail in , renin increases plasma [angiotensin II], a hormone that enhances NaCl and water retention by the kidneys. (Modified from Persson AEG et al. Acta Physiol Scand 2004;181:471.) 2.
Autoregulation is not perfect; RBF and GFR do change slightly as arterial blood pressure varies.
3.
Despite autoregulation, RBF and GFR can be changed by several hormones and by alterations in sympathetic nerve activity that change in response to alterations in the extracellular fluid volume (ECFV) (
Table 33.1
Regulation of Renal Blood Flow and Glomerular Filtration Rate
Table 33.1 ). As already discussed, the myogenic mechanism and tubuloglomerular feedback play key roles in maintaining RBF and GFR constant when blood pressure is greater that 90 mm Hg and ECFV is in the normal range. However, when the ECFV changes sympathetic nerves, angiotensin II, prostaglandins, NO, endothelin, bradykinin, ATP, and adenosine exert major control over RBF and GFR.
Fig.
33.21 shows how changes in efferent and afferent arteriolar resistance, mediated by changes in the hormones listed in
Table 33.1 , modulate both RBF and GFR.
The afferent and efferent arterioles are innervated by sympathetic neurons; however, sympathetic tone is minimal when ECFV is normal (see ). When ECFV is reduced, sympathetic nerves release norepinephrine and dopamine, and circulating epinephrine (a catecholamine-like norepinephrine and dopamine) is secreted by the adrenal medulla. Norepinephrine and epinephrine cause vasoconstriction by
Sympathetic nerves ↓ ECFV ↓↓ Angiotensin II ↓ ECFV ↓↓ Endothelin ↑ Stretch, A-II, bradykinin, epinephrine; ↓ ECFV ↓↓
Prostaglandins (PGE1, PGE2, PGI2) ↓ ECFV; ↑ shear stress, A-II No change/↑↑ Nitric oxide (NO) ↑ Shear stress, acetylcholine, histamine, bradykinin, ↑↑