Adenosine receptors and the kidney

Abstract

The autacoid, adenosine, is present in the normoxic kidney and generated in the cytosol as well as at extracellular sites. The rate of adenosine formation is enhanced when the rate of ATP hydrolysis prevails over the rate of ATP synthesis during increased tubular transport work or during oxygen deficiency. Extracellular adenosine acts on adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3)) in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate by constricting afferent arterioles, especially in superficial nephrons, and thus lowers the salt load and transport work of the kidney consistent with the concept of metabolic control of organ function. In contrast, it leads to vasodilation in the deep cortex and the semihypoxic medulla, and exerts differential effects on NaCl transport along the tubular and collecting duct system. These vascular and tubular effects point to a prominent role of adenosine and its receptors in the intrarenal metabolic regulation of kidney function, and, together with its role in inflammatory processes, form the basis for potential therapeutic approaches in radiocontrast media-induced acute renal failure, ischemia reperfusion injury, and in patients with cardiorenal failure.

Fig. 1

a–e Control of renal hemodynamics and transport by adenosine (ADO). The line plots illustrate the relationships between the given parameters. Small circles on these lines indicate ambient physiological conditions. In general, the medulla is at greater risk for hypoxic damage than the cortex due to a lower partial oxygen pressure (pO₂). a In every nephron segment, an increase in reabsorption or transport of sodium (T_Na) increases extracellular ADO. b ADO via A₁AR mediates tubuloglomerular feedback (TGF) and constricts the afferent arteriole to lower GFR. c In the proximal tubule, ADO via A₁AR stimulates T_Na and thus lowers the Na⁺ load to segments residing in the semihypoxic medulla. d In contrast, ADO via A₁AR inhibits T_Na in the medulla, including medullary thick ascending limb (mTAL). e In addition, ADO via A₂AR enhances medullary blood flow (MBF), which increases O₂ delivery and further limits O₂-consuming transport in the medulla (adapted from Vallon et al. 2006)

Fig. 2

a–e Adenosine is a mediator of the tubuloglomerular feedback: a proposed mechanism. Left panel: schematic drawing illustrating the macula densa (MD) segment at the vascular pole with the afferent arteriole (AA) entering and the efferent arteriole (EA) leaving the glomerulus; extraglomerular mesangium (EGM); glomerular basement membrane (BM); epithelial podocytes (EP) with foot processes (F); Bowman’s capsule (B) and space (BS), respectively; proximal tubule (PT). (Adapted from Kriz, Nonnenmacher and Kaissling). Right panel: schematic enlargement of area in rectangle. An increase in concentration-dependent uptake of Na⁺, K⁺ and Cl⁻ via the furosemide-sensitive Na⁺ − K⁺ − 2Cl⁻ cotransporter (NKCC2) a leads to transport-related, intra- and/or extracellular generation of adenosine (ADO) b, c. Extracellular ADO activates A₁AR, triggering an increase in cytosolic Ca²⁺ in extraglomerular mesangium cells (MC) d. The intensive coupling between extraglomerular MC, granular renin-containing cells, and vascular smooth muscle cells (VSMC) of the afferent arteriole by gap junctions allows propagation of the increased Ca²⁺ signal e, resulting in afferent arteriolar vasoconstriction and inhibition of renin release (adapted from Vallon et al. 2006)

Fig. 3

Schematic illustration of intrarenal mechanisms in acute renal failure. See text for further explanation (adapted from Osswald and Vallon 2008)

Fig. 4

a–d Basis for a therapeutic effect of A₁AR antagonism in heart failure. The basic effects of adenosine on renal functions are outlined in the legend to Fig. 1. a Heart failure can be associated with increased plasma concentrations of adenosine (ADO) and angiotensin II, and endothelial dysfunction can impair nitric oxide (NO) formation, all of which can enhance the A₁AR-mediated lowering of GFR and may, in addition, stimulate proximal reabsorption. b A₁AR antagonism induces natriuresis and diuresis by inhibiting proximal reabsorption and preserving or increasing GFR. c A₁AR antagonism can enhance sodium transport (T_Na) in semihypoxic medullary thick ascending limb (mTAL). This is prevented by coadministration of loop diuretics, and diuresis and natriuresis are potentiated. d A₂AR-mediated medullary vasodilation is preserved (adapted from Vallon 2008)