Considerable evidence has accumulated over the last decade implicating a role of cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) in the pathogenesis of hypertension. Indeed, 20-hydroxyeicosatetraenoic acid (20-HETE) is produced by vascular smooth muscle (VSM) cells and is a potent vasoconstrictor that depolarizes VSM by blocking large conductance Ca+-activated K2+ channels. In contrast, epoxyeicosatrienoic acids (EETs) are synthesized by the vascular endothelium and have opposite effects on VSM (hyperpolarization and vasodilatation). Inhibition of the synthesis of 20-HETE attenuates myogenic tone and autoregulation of blood flow and modulates vascular responses to vasodilators (NO and CO) and vasoconstrictors (angiotensin II, endothelin). In the kidney, 20-HETE inhibits sodium transport in the proximal tubule by blocking Na+-K+-ATPase activity. In the thick ascending limb of the loop of Henle, 20-HETE inhibits Na+-K+-2Cl- transport, in part, by blocking a 70 pS apical K+ channel. EETs are produced in the proximal tubule where they inhibit Na+-H+ exchange and in the collecting duct where they inhibit sodium and water transport. Numerous studies have established that the formation of EETs and 20-HETE and the expression of CYP enzymes are altered in the kidney in many genetic and experimental animal models of hypertension and in some forms of human hypertension. However, the functional significance of these changes remains to be determined. Given the importance of this pathway in the control of renal function and vascular tone, it is likely that alterations in the renal formation of CYP-dependent metabolites of AA will be shown to participate in the development of hypertension in many of these models.
This study examined the effect of transfer of overlapping regions of chromosome 5 that includes (4A(+)) or excludes (4A(-)) the cytochrome P-450 4A (CYP4A) genes from the Lewis rat on the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and the development of hypertension-induced renal disease in congenic strains of Dahl salt-sensitive (Dahl S) rats. The production of 20-HETE was higher in the outer medulla of 4A(+) than in Dahl S or 4A(-) rats. Mean arterial pressure (MAP) rose to 190 +/- 7 and 185 +/- 3 mmHg in Dahl S and 4A(-) rats fed a high-salt (HS) diet for 21 days but only to 150 +/- 5 mmHg in the 4A(+) strain. Protein excretion increased to 423 +/- 40 and 481 +/- 37 mg/day in Dahl S and 4A(-) rats vs. 125 +/- 15 mg/day in the 4A(+) strain. Baseline glomerular capillary pressure (Pgc) was lower in 4A(+) rats (38 +/- 1 mmHg) than in Dahl S rats (42 +/- 1 mmHg). Pgc increased to 50 +/- 1 mmHg in Dahl S rats fed a HS diet, whereas it remained unaltered in 4A(+) rats (39 +/- 1 mmHg). Baseline glomerular permeability to albumin (P(alb)) was lower in 4A(+) rats (0.19 +/- 0.05) than in Dahl S or 4A(-) rats (0.39 +/- 0.02). P(alb) rose to approximately 0.61 +/- 0.03 in 4A(-) and Dahl S rats fed a HS diet for 7 days, but it remained unaltered in the 4A(+) rats. The expression of transforming growth factor-beta2 was higher in glomeruli of Dahl S rats than in 4A(+) rats fed either a low-salt (LS) or HS diet. Chronic administration of a 20-HETE synthesis inhibitor (HET0016; 10 mg.kg(-1).day(-1) sc) reversed the fall in MAP and renoprotection seen in 4A(+) rats. These results indicate that the introgression of the CYP4A genes from Lewis rats into the Dahl S rats increases the renal formation of 20-HETE and attenuates the development of hypertension and renal disease.
Abstract-This study examined the role of changes in renal interstitial pressure on the renal levels of cytochrome P450 metabolites of arachidonic acid and compared the effects of inhibition of the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids with 1-aminobenzotriazole on the pressure-natriuretic response versus that seen after administration of HET0016, a more selective inhibitor of the formation of 20-HETE. Renal interstitial pressure rose by 3.4Ϯ0.3 mm Hg, and the levels of 20-HETE in renal cortical tissue doubled when renal perfusion pressure was increased from 100 to 160 mm Hg. Removal of the renal capsule prevented the increase in renal interstitial pressure and 20-HETE levels after an elevation in renal perfusion pressure. Urine flow and sodium excretion increased 5-fold when renal perfusion pressure was increased from 106 to 160 mm Hg. The administration of 1-aminobenzotriazole (50 mg/kg, IP) or HET0016 (10 mg/kg IV bolus plus 1 mg/kg per hour of infusion) decreased the pressure-natriuretic response by 50% and inhibited the renal formation of 20-HETE and epoxyeicosatrienoic acids by 90% and 50%, respectively. Administration of a lower dose of HET0016 (1 mg/kg per hour, IV) selectively reduced the formation of 20-HETE by 80% without inhibiting renal epoxygenase activity and blunted the pressure-natriuretic response by 42%. These results indicate that elevations in renal perfusion pressure increase 20-HETE levels in the kidney secondary to a rise in renal interstitial pressure. They also suggest that 20-HETE, rather than epoxyeicosatrienoic acids, modulates the pressure-natriuretic response, because selective blockade of the formation of 20-HETE with HET0016 blunts the response to the same extent as that seen after inhibition of the formation of 20-HETE and epoxyeicosatrienoic acids with 1-aminobenzotriazole. T he concept that the kidney plays an essential role in the long-term control of arterial pressure is based on the pressure-natriuretic response; however, the mechanism by which this occurs is unknown. 1,2 Previous studies have indicated that pressure natriuresis is associated with elevations in medullary blood flow 3-6 and renal interstitial hydrostatic pressure (RIHP) 7-13 and a fall in sodium transport in the proximal tubule. 14 -18 The fall in sodium transport is associated with inhibition of Na ϩ K ϩ -ATPase activity and internalization of sodium/hydrogen exchanger from the brush border. 19,20 The rise in RIHP seems to be important in triggering pressure natriuresis, because removal of the renal capsule blocks the fall in proximal tubular reabsorption and attenuates the natriuretic response after an elevation in renal perfusion pressure (RPP). 7-13 However, the mechanism by which elevations in RPP and/or RIHP inhibits sodium transport in the proximal tubule remains to be determined.Recent studies have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid (AA) may be involved. 19,20 In this regard, chronic blockade of the formation of epoxyeico...
This review summarizes recent findings that address the issue of whether cytochrome P-450 metabolites of arachidonic acid play an important role in the regulation of renal tubular and peripheral vascular function and contribute to the pathogenesis of hypertension.
The present study examined whether transfer of overlapping regions of chromosome 5 that include (4A ϩ ) or exclude the cytochrome P-450 (CYP) 4A genes from the Lewis rat alters the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and/or the development of hypertension in congenic strains of Dahl salt-sensitive (S) rats. The expression of CYP4A protein and the production of 20-HETE in the renal outer medulla was greater in the 4A ϩ congenic strain than the levels seen in S rats or in overlapping control congenic strains that exclude the CYP4A region. Mean arterial pressure (MAP) rose from 122 Ϯ 2 to 190 Ϯ 7 mmHg in S rats and from 119 Ϯ 2 and 123 Ϯ 2 to 189 Ϯ 7 and 187 Ϯ 3 mmHg in the two control congenic strains fed an 8.0% NaCl diet for 3 wk. In contrast, MAP only increased from 112 Ϯ 2 to 150 Ϯ 5 mmHg in the 4A ϩ congenic strain. Chronic blockade of the formation of phenyl-NЈ-hydroxyimido formamide (TS-011; 1 mg/kg bid) restored the salt-sensitive phenotype in the 4A ϩ congenic strain and MAP rose to 181 Ϯ 6 mmHg after an 8.0% NaCl dietary challenge. TS-011 had no effect on the development of hypertension in S rats or the two control congenic strains. The pressure-natriuretic and diuretic responses were fivefold greater in the 4A ϩ congenic strain than in S rats. These results indicate that transfer of the region of chromosome 5 between markers D5Rat108 to D5Rat31 from the Lewis rat into the Dahl S genetic background increases the renal production of 20-HETE, improves pressure-natriuresis and opposes the development of salt-induced hypertension.cytochrome P-450; kidney; 20-HETE RENAL TRANSPLANTATION STUDIES have indicated that some form of renal dysfunction underlies the development of hypertension in humans and in experimental animal models (4, 9, 10, 21). However, the factors responsible for altering kidney function and the genes involved remain to be determined. Several lines of evidence suggest that a deficiency in the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the development of hypertension in Dahl salt-sensitive (S) rats. In this regard, 1) the formation of 20-HETE and the expression of cytochrome P-450 (CYP) enzymes of the 4A family is reduced in the outer medulla and the thick ascending limb of the loop of Henle (TALH) of S rats (13, 17); 2) 20-HETE is an endogenously-formed inhibitor of Cl Ϫ transport in the TALH and Na ϩ and Cl Ϫ reabsorption is elevated in this segment of the nephron in S rats (13,15,31); 3) 20-HETE modulates tubuloglomerular feedback (TGF) responses (32) and glomerular hemodynamics is altered in S rats (14, 26, 28); 4) increasing the renal formation of 20-HETE with fibrates or the SOD mimetic Tempol, lowers blood pressure (BP) and improves renal function in S rats (12, 29); and 5) inhibitors of the formation of 20-HETE blunts the pressure-natriuretic response (5) and promotes the development of salt-sensitive hypertension in normotensive strains of rats (11,25).These studies suggest that the renal formation of 20-HETE is reduced in S ...
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