The signaling importance of adenosine in tubuloglomerular feedback (TGF) is highlighted by the absence of TGF in mice lacking the adenosine receptor (A1). Research has demonstrated that an increase in glomerular filtration rate (GFR) leads to a rise in NaCl concentration in tubular fluid at the macula densa. Consequently, more NaCl enters cells through the NKCC2 symporter located in the apical plasma membrane. This increase in intracellular NaCl stimulates the release of ATP and adenosine. Adenosine binds to A1 receptors while ATP binds to P2X receptors on the plasma membrane of smooth muscle cells in the afferent arteriole. Both hormones elevate intracellular Ca++, resulting in vasoconstriction of the afferent artery and a subsequent decrease in GFR. Adenosine, unlike in other vascular beds, constricts the afferent arteriole in the kidney.

α1-adrenoceptors, mainly found in afferent arterioles, are bound by norepinephrine, which leads to decreased renal blood flow (RBF) and GFR. Dehydration or intense emotional stimuli activate sympathetic nerves and cause a reduction in RBF and GFR.

Angiotensin II is produced systemically and locally within the kidneys. It constricts both the afferent and efferent arterioles, resulting in decreased RBF and GFR. The efferent arteriole exhibits higher sensitivity to angiotensin II compared to the afferent arteriole. Therefore, at low concentrations of angiotensin II, constriction of the efferent arteriole predominates, leading to an increase in GFR and a decrease in RBF. However, at high concentrations of angiotensin II, both the afferent and efferent arterioles constrict, resulting in decreased GFR and RBF.

Individuals with renal artery stenosis, caused by atherosclerosis, often experience elevated systemic arterial blood pressure due to the renin-angiotensin system. The stenosis increases pressure in the renal artery proximal to it, while pressure distal to the stenosis remains normal or decreases. Autoregulation plays a crucial role in maintaining RBF, glomerular capillary pressure (PGC), and GFR in the presence of this stenosis. Administering drugs to lower systemic blood pressure also reduces the pressure distal to the stenosis, leading to a decrease in RBF, PGC, and GFR.

Significant hemorrhage reduces extracellular fluid volume (ECFV) and arterial blood pressure, activating sympathetic innervation of the kidneys through the baroreceptor reflex.
ATP Bradykinin ↑ Prostaglandins, ↓ ACE ↑↑ Natriuretic peptides (ANP, BNP) ↑ ECFV ↑ No change
A-II, angiotensin II; ACE, angiotensin-converting enzyme; ECFV, extracellular fluid volume.
Tubuloglomerular feedback (TGF) is absent in mice that do not express the adenosine receptor (A1). This underscores the importance of adenosine signaling in TGF. Studies have shown that when GFR increases and causes the concentration of NaCl in tubular fluid at the macula densa to rise, more NaCl enters cells via the 1Na+-1K+-2Cl− symporter (NKCC2) located in the apical plasma membrane (see
Fig.
33.20 ). Increased intracellular [NaCl] in turn stimulates release of ATP via ATP-conducting ion channels located in the basolateral membrane of macula densa cells. In addition, adenosine production is also enhanced. Adenosine binds to A1 receptors and ATP binds to P2X receptors located on the plasma membrane of smooth muscle cells in the afferent arteriole. Both hormones increase intracellular [Ca++], which causes vasoconstriction of the afferent artery and therefore a fall in GFR. Although adenosine is a vasodilator in most other vascular beds, it constricts the afferent arteriole in the kidney.
binding to α1-adrenoceptors, which are located mainly in afferent arterioles. Activation of α1-adrenoceptors decreases RBF and GFR. Dehydration or strong emotional stimuli (e.g., fear, pain) also activate sympathetic nerves and reduce RBF and GFR.
Angiotensin II is produced systemically as well as locally within the kidneys. It constricts the afferent and efferent arterioles and decreases both RBF and GFR.
Fig. 33.22 shows how norepinephrine, epinephrine, and angiotensin II act together to decrease RBF and GFR and thereby dThe efferent arteriole is more sensitive than the afferent arteriole to angiotensin II. Therefore with low concentrations of angiotensin II, constriction of the efferent arteriole predominates, and GFR increases and RBF decreases. However, with high concentrations of angiotensin II, constriction of both afferent and efferent arterioles occurs, and GFR and RBF both decrease (see
Fig. 33.21
Individuals with renal artery stenosis (narrowing of the lumen of the artery) caused by atherosclerosis, for example, often have elevated systemic arterial blood pressure mediated by the renin-angiotensin system. Pressure in the renal artery proximal to the stenosis is increased, but pressure distal to the stenosis is normal or reduced. Autoregulation is important in maintaining RBF, PGC, and GFR in the presence of this stenosis. Administration of drugs to lower systemic blood pressure also lowers the pressure distal to the stenosis; accordingly, RBF, PGC, and GFR fall.
Significant hemorrhage decreases ECFV and arterial blood pressure and therefore activates sympathetic innervation of the kidneys via the baroreceptor reflex (