Hypertension and Beyond
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This review highlights milestones leading to the discovery that 20-hydroxyeicosatetraenoic acid (20-HETE) plays a critical role in the regulation of renal function, vascular tone, and the development of hypertension and cardiovascular disease. Our interest in this pathway emerged 30 years ago. At that time, we were studying mechanisms of pressure natriuresis and factors that reset this response in hypertension. The results indicated that pressure natriuresis is associated with elevations in renal medullary blood flow and interstitial pressure that inhibit sodium transport in the proximal tubule (PT) and thin descending loop of Henle.1 The pressure–natriuretic response was shifted to higher pressures in spontaneously hypertensive rat (SHR) and Dahl salt-sensitive (S) rats. Resetting of the response in SHR was because of elevated renal vascular resistance. Renal hemodynamics were relatively normal in Dahl S rats, and the blunted natriuretic response was because of elevated sodium transport in the thick ascending loop of Henle (TALH).2 However, the factors that reset this relationship were unknown.
As presented in Figure 1, we were intrigued with the finding that arachidonic acid could be metabolized by renal cytochrome P450 (CYP) enzymes to 20-HETE.3,4 Before this, only cyclooxygenase and lipoxygenase enzymes were known to metabolize arachidonic acid, and the CYP enzymes responsible for ω-hydroxylation of fatty acids were thought to be only expressed in the liver. Iwai and Inagami5 then reported that Cyp4a2 mRNA that produces 20-HETE is differentially expressed in the kidney of Wistar Kyoto and SHR, and Sacerdoti et al6 found that synthesis of 20-HETE in the kidney was elevated in SHR. This was followed by a seminal report that treating SHR with stannous chloride reduced renal 20-HETE and attenuated hypertension.7 However, subsequent studies suggested that the observed fall in blood pressure might be because of induction of …