Increased Renal Proximal Convoluted Tubule Transport Contributes to Hypertension in Cyp4a14 Knockout Mice

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Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 8,11,, a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5a-dihydrotestosterone increased BP and induced both Cyp4a12 expression and 20-HETE levels in preglomerular microvessels. Administration of a 20-HETE antagonist prevented and reversed the effects of dihydrotestosterone on BP. Cyp4a14(2/2) mice, which exhibit androgen-sensitive hypertension in the male mice, produced increased levels of vascular 20-HETE; furthermore, administration of a 20-HETE antagonist normalized BP. To examine whether androgen-independent increases in 20-HETE are sufficient to cause hypertension, we studied Cyp4a12-transgenic mice, which express the CYP4A12-20-HETE synthase under the control of a doxycycline-sensitive promoter. Administration of doxycycline increased BP by 40%, and administration of a 20-HETE antagonist prevented this increase. Levels of CYP4A12 and 20-HETE in preglomerular microvessels of doxycycline-treated transgenic mice approximately doubled, correlating with increased 20-HETE-dependent sensitivity to phenylephrine-mediated vasoconstriction and with decreased acetylcholine-mediated vasodilation in the renal microvasculature. We observed a similar contribution of 20-HETE to myogenic tone in the mesenteric microvasculature. Taken together, these results suggest that 20-HETE both mediates androgeninduced hypertension and can cause hypertension independent of androgen. 24: 128824: -129624: , 201324: . doi: 10.1681 The v-hydroxylation of arachidonic acid (AA) to 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) is catalyzed by members of the cytochrome P450 4 (CYP4) gene family and regulated by factors such as age, sex hormones, and dietary lipids. 1,2 CYP4 expression and 20-HETE synthesis have been implicated in the regulation of vascular and tubular function and the development of hypertension in experimental models. [3][4][5] Studies demonstrating that 20-HETE is a vasoconstrictor [6][7][8] suggest that increased 20-HETE synthesis and/or effects in the renal vasculature underlies its prohypertensive property. [9][10][11][12] This notion has been substantiated by several reports showing the following: (1) the synthesis of and vascular reactivity to 20-HETE are significantly higher in spontaneously hypertensive rats (SHRs), 13,14 (2) inhibition of vascular 20-HETE synthesis by CYP4A2 antisense oligonucleotides decreases BP in SHRs, 15,16 J Am Soc Nephrol

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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Androgen-Sensitive Hypertension Associates with Upregulated Vascular CYP4A12–20-HETE Synthase

Mei

Cheng

et al. 2013

Self Cite

“…21,22 We and others have shown that disruption of the Cyp4a14 gene in mice results in androgen-dependent hypertension due to increased Cyp4a12 expression and 20-HETE biosynthesis in Cyp4a14KO male mice. 17 Increased expression of the sodium-hydrogen exchanger NHE3 and increased fluid reabsorption in proximal tubules contribute to the Cyp4a14KO hypertensive phenotype, 27 although endothelial nitric oxide synthase uncoupling, increased oxidative stress, and consequent vasoconstriction have been also postulated as a major cause of hypertension in these mice. 28 We show that castration results in reduced renal 20-HETE biosynthesis and BP and protects Cyp4a14KO mice from diabetic-mediated renal injury.…”

Section: Discussionmentioning

confidence: 99%

Hypertension Is a Major Contributor to 20-Hydroxyeicosatetraenoic Acid–Mediated Kidney Injury in Diabetic Nephropathy

Gangadhariah

Luther

García

et al. 2015

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In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetesmediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.

“…[20][21][22] In parallel, we demonstrate that the renal content of 20-HETE exhibits a clear circadian pattern and that this pattern is significantly modified in kidneys of clock(2/2) mice. 20-HETE has a potent prohypertensive effect by acting as a vasoconstrictor of preglomerular arterioles, but it can also inhibit several important sodium transporters in the proximal tubule and the thick ascending limb (Na + -K + -adenosine triphosphatase, NHE3, NKCC2 Na 1 -K + -Cl 2 cotransporter 2), [23][24][25][26] thereby promoting sodium excretion and lowering BP. 20-HETE is mainly produced by a Cyp4a subfamily of enzymes located in both microvessels and tubular cells.…”

Section: Discussionmentioning

confidence: 99%

The Circadian Clock Modulates Renal Sodium Handling

Nikolaeva

Pradervand

Centeno³

et al. 2012

124

122

The circadian clock contributes to the control of BP, but the underlying mechanisms remain unclear. We analyzed circadian rhythms in kidneys of wild-type mice and mice lacking the circadian transcriptional activator clock gene. Mice deficient in clock exhibited dramatic changes in the circadian rhythm of renal sodium excretion. In parallel, these mice lost the normal circadian rhythm of plasma aldosterone levels. Analysis of renal circadian transcriptomes demonstrated changes in multiple mechanisms involved in maintaining sodium balance. Pathway analysis revealed the strongest effect on the enzymatic system involved in the formation of 20-HETE, a powerful regulator of renal sodium excretion, renal vascular tone, and BP. This correlated with a significant decrease in the renal and urinary content of 20-HETE in clockdeficient mice. In summary, this study demonstrates that the circadian clock modulates renal function and identifies the 20-HETE synthesis pathway as one of its principal renal targets. It also suggests that the circadian clock affects BP, at least in part, by exerting dynamic control over renal sodium handling. Recent evidence indicates that the circadian clock is involved in BP control. In mice, suppression or decrease of the circadian clock activity via deletion of the circadian transcriptional activators Bmal1, Clock, or Npas2 leads to low BP, whereas its constitutive activation via deletion of the circadian repressors Cry1 and Cry2 results in salt-sensitive hypertension. 1-4 Wang et al. have recently shown that mice simultaneously devoid of three prolineand acidic amino acid-rich basic leucine zipper circadian transcriptional factors Dbp, Hlf, and Tef exhibit a significant reduction in BP. 5 Maintaining BP within the normal range strongly depends on the capacity of the kidney to precisely regulate sodium content in the extracellular space. Thus, dysregulation of molecular mechanisms involved in renal sodium handling could be partially responsible for the elevated or decreased BP observed in mice with genetically altered clocks. This hypothesis is supported by evidence in humans suggesting that alteration of circadian rhythms of urinary sodium excretion is the primary cause of disease in several forms of hyper-or hypotension. For instance, a decreased renal capacity to excrete sodium during the daytime correlates with nocturnal hypertension, whereas increased sodium excretion during the nighttime contributes to the maintenance of orthostatic hypotension. 6,7 Of note, important changes in the amplitude or the circadian phase of urinary excretion of sodium can be provoked not only by a pathologic process but also by a misalignment between the endogenous circadian clock and the imposed rest-activity or feeding cycles, or by sleep disturbance. For instance, Kamperis et al. have shown that acute sleep deprivation in humans leads to excessive natriuresis and kaliuresis during the subjective night and attenuation of the