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Salt has been used as a food preservative and part of the human diet for thousands of years. Consequently human dietary sodium chloride intake is significantly higher than that needed to sustain life. Fortunately, kidneys function to regulate sodium chloride excretion to maintain proper levels of sodium chloride and extracellular volume when dietary salt intake changes. If the kidneys are properly functioning then an increase in dietary salt intake results in increased sodium chloride excretion (natriuresis) and extracellular fluid volume remains unchanged. On the other hand, if the kidneys do not function properly to excrete sodium chloride then extracellular fluid volume expansion occurs and an elevation in blood pressure is required to bring extracellular fluid volume and plasma sodium back to homeostatic levels.
The report by Liclican et al.1 in this issue of Hypertension provides convincing evidence that a properly functioning axis that includes adenosine 2A (A2A) receptors and epoxyeicosatrienoic acids (EETs) is required for the kidneys to respond to increased dietary salt intake.
A balance between salt intake and salt excretion is maintained by a coordinated effort that relies heavily on proper kidney function. When dietary salt intake is increased there are neural, hormonal and paracrine factors as well as the proper function of renal blood vessels and tubular epithelial cell transporters working in unison to excrete the excess salt. EETs have been demonstrated to be an essential component of this coordinated renal natriuretic response. High dietary salt has been demonstrated to increase renal cytochrome P450 2C (CYP2C) enzymes that are responsible for generating EETs2-4. Pharmacological inhibition or genetic manipulation to decrease CYP2C enzymes results in dietary high salt-induced elevations in blood pressure.2-4 Likewise, salt-sensitive animal models of hypertension demonstrate an inability to increase renal CYP2C expression in response to a high salt diet2-4.
The findings by Liclican et al.1 in this issue of Hypertension further demonstrate in Dahl salt-resistant (SR) rats that increasing dietary salt increased EET levels in the renal cortex and medulla. Additional evidence is presented that A2A receptor activation is required for the increase in renal EET levels in response to high dietary salt intake. When the A2A receptor antagonist, ZM241385 was administered to Dahl SR rats renal EETs did not increase and blood pressure did increase in response to high dietary salt. These findings are in agreement with previous studies conducted by this group demonstrating that Dahl SR but not Dahl salt-sensitive (SS) rats had an increase in renal cortical and medulla CYP2C and adenosine A2A receptor expression in response to a high salt diet5. This previous study also demonstrated that the Dahl SS rats did not increase renal EETs in response to a non-selective adenosine analog5. Therefore an axis of A2A receptors to EETs is required for the kidneys to properly respond to increased dietary salt intake.
The exact mechanism responsible for A2A receptor regulation and activation in response to a high salt diet responsible for the natriuresis remain speculative. There is clear evidence that increased renal expression of the A2A receptors are required for the natriuresis in response to increased dietary salt1,5. What is less clear is whether or not increases in renal adenosine levels are necessary for the kidney to increase sodium excretion. Urinary purine levels increase in Dahl SR but not in Dahl SS rats in response to high dietary salt5. Then again, urinary purine levels and plasma adenosine levels are elevated in Dahl SS compared to Dahl SR rats5. Thus, renal A2A receptor activation is required but it is still not clear if increased adenosine levels are necessary for the natriuretic response in the Dahl SR rat.
A2A receptor activation and subsequent EET actions at the renal vascular and tubular levels could operate in concert to produce increased sodium excretion (Figure 1). One aspect thought to be necessary for increased sodium excretion in response to dietary salt is an increase in renal blood flow. Renal preglomerular microvessel dilation occurs in response to A2A receptor activation or EETs6. Recent studies also demonstrated that synthesized EETs are necessary for the renal vasodilation to adenosine and A2A receptor activation6-8. Based on these findings one can postulate that the increased renal CYP2C expression observed does not require A2A receptor activation but is required for natriuresis in response to a high salt diet. Interestingly, adenosine mediated dilation in the cerebral circulation has been linked to adenosine 2B (A2B) receptor activation and the synthesis and release of EETs9. The possible contribution of the A2B as well as other adenosine receptors to renal hemodynamics in response to a high salt diet remains unknown.
Another aspect that is necessary for increased sodium excretion in response to dietary salt is decreased tubular sodium reabsorption. Interestingly A2A receptors and EETs could interact on tubular sodium transport to contribute to natriuresis. CYP2C protein expression in rat cortical collecting duct (CCD) and thick ascending limb (TAL) increases and decreases in response to corresponding changes in dietary sodium10. Additionally, patch-clamp experiments conducted in rat CCD cells have demonstrated that 11,12-EET inhibits epithelial sodium channel (ENaC) activity10,11. However, adenosine activation of the adenosine1 (A1) but not the A2A receptors was linked to the ability of EETs to inhibit CCD ENaC activity11. Thus the contribution of the A1 receptors and 11,12-EET inhibition of ENaC to the natriuretic response to high dietary salt require further investigation.
The report by Liclican et al.1 provides evidence that the A2A receptors – EETs axis is required for the kidneys to maintain proper sodium balance and blood pressure in the face of elevated dietary salt. If this axis is not properly functioning then an elevated blood pressure is required to maintain sodium balance. The questions that remain are whether or not increased renal adenosine levels are required for this response, the specific renal tubular and vascular mechanisms responsible and whether other adenosine receptors participate in the natriuretic response. These questions are critical since the potential use of adenosine receptor based therapies for the treatment of infection, autoimmunity, ischemia and neurodegenerative diseases are moving towards clinical use in humans12. The findings of the study by Liclican et al.1 in this issue of Hypertension makes A2A receptors and EETs stronger candidates as therapeutic targets for salt-sensitive hypertension.
Sources of Funding
This work was supported by Advancing a Healthier Wisconsin and National Institutes of Health (NIH) grants HL-59699 and DK38226.
U.S. Patent #7,550,617