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Maintaining Balance Under Pressure: Integrated Regulation of Renal Transporters During Hypertension

Hypertension is the leading cause of stroke and cardiovascular diseases and a leading risk factor for global disease burden, affecting 30% of the adult population in Western cultures.1 Blood pressure (BP) can be elevated by vasoconstriction and by increasing the circulating volume. Evidence from studies of mutations in renal Na+ transporters, renal transplantation, and diuretic action supports Guyton’s hypothesis that long-term regulation of effective circulating volume and BP depends on fractional renal Na+ reabsorption.2–4 Ultimately, excess Na+ reabsorption (Figure, red arrows) raises effective circulating volume and BP which provoke counteracting natriuretic responses to match Na+ output to Na+ intake at the expense of elevated BP (Figure, blue arrow).2 We and others have determined that pressure natriuresis responses involve Na+ transporter inhibition at multiple levels of regulation.5–13 According to Guyton, kidneys possess the capacity to excrete enough Na+ and volume to normalize BP in the face of expanded effective circulating volume.2 Thus, hypertension can be characterized as a failure of compensatory renal pressure natriuresis. Indeed, there is strong evidence that the pressure natriuresis response is impaired during experimental hypertension by inflammation, immune cell infiltration, and intrarenal angiotensin II (AngII) production, secondary to initiating stimuli such as AngII infusion, reduced NO production, high-salt diet, or elevated renal sympathetic nerve activity.14–17 This brief review focuses on the natriuretic effectors and addresses (1) the renal tubular locations and transporters that participate in pressure natriuresis and (2) the mechanisms that blunt the response in experimental models of hypertension.



Figure. 
Renal transporter profile reveals region specific transporter regulation during experimental hypertension. A , Anatomic arrangement of renal cortex and renal medulla in a kidney cross-section …