Proximal tubular-targeted overexpression of the Cyp4a12-20-HETE synthase promotes salt-sensitive hypertension in male mice.
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ABSTRACT:
SUBMITTER: Gilani A
PROVIDER: S-EPMC7468799 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5α-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(-/-) 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 androgen-induced hypertension and can cause hypertension independent of androgen.
| S-EPMC3736709 | biostudies-literature
Project description:The role of proximal tubule (PT) angiotensinogen (AGT) in modulating blood pressure has previously been examined using mice expressing PT human AGT and human renin, or rat AGT. These animals are hypertensive; however, the question remains whether alterations in mouse PT AGT alone affects arterial pressure.Mouse AGT cDNA was knocked-in to the endogenous kidney androgen protein (KAP) gene using an internal ribosomal entry site (IRES)-based strategy.The KAP-mAGT animals showed kidney-specific KAP-AGT mRNA expression; renal in situ hybridization detected KAP-AGT mRNA only in PT. Urinary AGT was markedly increased in KAP-mAGT mice. On a high Na diet, radiotelemetric arterial pressure showed a systolic pressure elevation; no significant difference in arterial pressure was observed on a normal diet. Plasma renin concentration (PRC) was reduced in KAP-mAGT animals given a high Na diet, but was not different between mouse lines during normal Na intake. Plasma AGT concentration was not altered by overexpression of PT mouse AGT.In summary, PT overexpression of mouse AGT leads to salt-sensitive hypertension without recruitment of the systemic renin-angiotensin system.
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Project description:Human blood pressure salt sensitivity is associated with changes in urinary metabolites related to fumarase (Fh) and nitric oxide (NO) metabolism, and fumarase promotes NO production through an arginine regeneration pathway. We examined the role of the fumarase-NO pathway in the development of hypertension using genetically engineered rat models. Dahl salt-sensitive (SS) rats with heterozygous mutation of eNOS (endothelial NO synthase or Nos3; SS-Nos3+/-) were bred with SS rats with a hemizygous Fh transgene. SS-Nos3+/- rats without the Fh transgene (SS-Nos3+/-/Fh0/0) developed substantial hypertension with a mean arterial pressure of 134.2±3.7 mm?Hg on a 0.4% NaCl diet and 178.0±3.5 mm?Hg after 14 days on a 4% NaCl diet. Mean arterial pressure decreased remarkably to 123.1±1.4 mm?Hg on 0.4% NaCl, and 143.3±1.5 mm?Hg on 4% NaCl in SS-Nos3+/- rats with a Fh transgene (SS-Nos3+/-/Fh0/1), and proteinuria, renal fibrosis, and tubular casts were attenuated in SS-Nos3+/-/Fh0/1 rats compared with SS-Nos3+/-/Fh0/0 rats. eNOS protein abundance decreased in rats with the Nos3 heterozygous mutation, which was not influenced by Fh overexpression in rats on the 0.4% NaCl diet. However, the decrease in NO metabolite in the renal outer medulla of SS-Nos3+/-/Fh0/0 rats on the 0.4% NaCl diet was reversed in SS-Nos3+/-/Fh0/1 rats, and levels of L-arginine, but not the other 12 amino acids analyzed, were significantly higher in SS-Nos3+/-/Fh0/1 rats than in SS-Nos3+/+/Fh0/0 rats. In conclusion, fumarase has potent effects in restoring NO production and blunting the development of hypertension attributable to eNOS haploinsufficiency.
| S-EPMC6620137 | biostudies-literature
Project description:Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the ?1-subunit of the NO receptor soluble guanylate cyclase (sGC?1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGC?1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male sGC?1 (-/-)S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4a12a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGC?1 (-/-)S6 than of male sGC?1 (-/-)B6 mice. Furthermore, treating male sGC?1 (-/-)S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGC?1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGC?1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.
| S-EPMC4935526 | biostudies-literature
Project description:20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a (11)C-labeled specific 20-HETE synthase inhibitor, N'(4-dimethylaminohexyloxy)phenyl imidazole ([(11)C]TROA). Autoradiographic study showed that [(11)C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [(11)C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [(11)C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [(11)C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.
| S-EPMC3434634 | biostudies-literature
Project description:Hypertension is the most common modifiable risk factor for stroke, and understanding the underlying mechanisms of hypertension and hypertension-related stroke is crucial. 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE), which plays an important role in vasoconstriction, autoregulation, endothelial dysfunction, angiogenesis, inflammation, and blood-brain barrier integrity, has been linked to hypertension and stroke. 20-HETE can promote hypertension by potentiating the vascular response to vasoconstrictors; it also can reduce blood pressure by inhibition of sodium transport in the kidney. The production of 20-HETE is elevated after the onset of both ischemic and hemorrhagic strokes; on the other hand, subjects with genetic variants in CYP4F2 and CYP4A11 that reduce 20-HETE production are more susceptible to stroke. This review summarizes recent genetic variants in CYP4F2, and CYP4A11 influencing 20-HETE production and discusses the role of 20-HETE in hypertension and the susceptibility to the onset, progression, and prognosis of ischemic and hemorrhagic strokes.
| S-EPMC6770042 | biostudies-literature
Project description:Androgen plays an important role in blood pressure regulation. Epidemiological studies have shown that men have a higher prevalence for developing hypertension than aged-matched, premenopausal women. Interestingly, postmenopausal women and women with polycystic ovary syndrome, both of which have increased endogenous androgen production, have elevated risks for hypertension suggesting that androgen may contribute to its development. Studies from our laboratory and others have provided substantial evidence that 20-hydroxyeicosatetraenoic acid (20-HETE) mediates the hypertension seen in rodents treated with androgen. 20-HETE is the cytochrome P450 (CYP)-derived ω-hydroxylated metabolite of arachidonic acid. 20-HETE plays a complex role in blood pressure regulation. In the kidney tubules, 20-HETE decreases blood pressure by promoting natriuresis, while in the microvasculature it has a pressor effect. In the microcirculation, 20-HETE participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor stimuli and contributes to myogenic, mitogenic and angiogenic responses. In addition, 20-HETE acts on the endothelium to promote endothelial dysfunction and endothelial activation. Recently, we have demonstrated that 20-HETE induces endothelial ACE thus setting forth a potential feed forward mechanism through activation of the renin-angiotensin-aldosterone system. In this review, we will discuss the pro-hypertensive effects of 20-HETE and its role in androgen-induced vascular dysfunction and hypertension.
| S-EPMC3248593 | biostudies-literature
Project description:Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, β-, and γ-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1β expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1β expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1β mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1α-knockout (NOS1αKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P<0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P<0.01) fed a high-salt diet. These results indicate that NOS1β is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.
| S-EPMC4978040 | biostudies-literature
Project description:Objective20-Hydroxyeicosatetraenoic acid (20-HETE) is a vasoactive eicosanoid exhibiting effects on vascular smooth muscle cell (VSMC) via G-protein coupled receptor 75 (GPR75) and include stimulation of contractility, migration, and growth. We examined whether VSMC-targeted overexpression of CYP4A12, the primary 20-HETE-producing enzyme in mice, is sufficient to promote hypertension.MethodsMice with VSM-specific Cyp4a12 overexpression (Myh11-4a12) and their littermate controls (WT) were generated by crossbreeding Cyp4a12-floxed with Myh11-Cre mice. The 20-HETE receptor blocker, N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide (AAA), was administered in the drinking water. Experiments were carried out for 12 days. SBP was measured by tail cuff. Renal interlobar and mesenteric arteries were harvested for assessment of gene expression, 20-HETE levels, vascular contractility, vasodilation, and remodeling.ResultsVascular and circulatory levels of 20-HETE were several folds higher in Myh11-4a12 mice compared with WT. The Myh11-4a12 mice compared with WT were hypertensive (145 ± 2 vs. 127 ± 2 mmHg; P < 0.05) and their vasculature displayed a contractile phenotype exemplified by increased contractility, reduced vasodilatory capacity, and increased media to lumen ratio. All these features were reversed by the administration of AAA. The mechanism of increased contractility includes, at least in part, Rho-kinase activation followed by increased myosin light chain phosphorylation and activation of the contractile apparatus.ConclusionVSM-specific Cyp4a12 overexpression is sufficient to alter VSM cell phenotype through changes in contractile markers and enhancement in contractility that promote hypertension and vascular dysfunction in a 20-HETE-dependent manner. The 20-HETE receptor GPR75 may represent a novel target for the treatment of hypertension and associated vascular conditions.
| S-EPMC8820380 | biostudies-literature
Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.
2024-07-10 | GSE269511 | GEO