Aldosterone antagonism does not attenuate the development of malignant hypertension in Cyp1a1-Ren2 transgenic rats
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Previously, we reported that inhibition of CYP1B1 with 2, 4, 3′, 5′‐tetramethoxystilbene (TMS) in rats prevented the development and maintenance of angiotensin II (Ang II)‐induced hypertension. We have found that TMS (300 μg/kg, i.p. every 3 rd day) also reduces mean arterial pressure (MAP) in DOCA/Salt‐hypertensive rats (154 ± 1 mmHg to 96 ± 1 mmHg, P < 0.05) and in spontaneously hypertensive rats (163 ± 14 mmHg to 116 ± 4 mmHg, P < 0.05). To further elucidate the role of CYP1B1 in hypertension, studies were conducted in CYP1B1 knockout (CYP1B1 −/− ) and wild‐type (CYP1B1 +/+ ) mice. Ang II infused by mini osmotic pumps (1mg/kg/min sc.) for 13 days produced a significantly smaller increase in MAP (P < 0.05) in CYP1B1 −/− mice (112 ± 1 to 128 ± 2 mmHg) than in CYP1B1 +/+ mice (113 ± 3 mmHg to 158 ±3 mmHg). In Ang II‐treated CYP1B1 +/+ mice, responses of the mesenteric artery to phenylephrine and endothelin‐1, media to lumen ratio and aortic ROS production were significantly increased compared to Ang II‐treated CY1B1 −/− mice. Administration of DOCA (35 mg/kg/week im. + 1% NaCl in drinking water) increased MAP from 102 ± 1 to 153 ± 4 mmHg in CYP1B1 +/+ but not in CYP1B1 −/− mice. These data suggest that CYP1B1 contributes to the development of hypertension, most likely via increased ROS generation and vascular reactivity and hypertrophy, and could serve as a novel target for the development of agents like TMS for the treatment of hypertension.
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Aldosterone synthase
Diabetic Cardiomyopathy
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Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10-/- mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10-/- mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease.
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17β-estradiol (E2) via its cytochrome P450 (CYP) 1B1 generated metabolite 2-methoxyestradiol (2ME) protects from angiotensin (Ang) II-induced hypertension in female mice. Gene disruption of 12/15 lipoxygenase (LOX) that metabolizes arachidonate (A) into 12(S)- and 15(S)-HETE minimizes Ang II-induced hypertension in male mice. We performed this study to determine if 2-ME generated by CYP1B1 from E2 mediates its protective effect against Ang II-induced hypertension via LOX inhibition in female mice. Systolic blood pressure (SBP, mmHg, tail-cuff) in response to Ang II (700 ng/Kg/min, sc, miniosmotic pump, 2 weeks) was greater ( P <0.05, n=4-5) in ovariectomized (OVX) than intact Cyp1b1 +/+ / Alox15 +/+ (174±2 vs 135±5), and intact or OVX- Cyp1b1 +/+ / Alox15 –/– (120±4 and 125±5) mice. Moreover, SBP in response to Ang II was greater in trans-2,3',4,5'-tetramethoxystilbene (CYP1B1 inhibitor, 300 μg/Kg, every 3rd day, ip)-treated intact Cyp1b1 +/+ / Alox15 +/+ than Cyp1b1 +/+ / Alox15 –/– (164±3 vs 132±3, n=6-8, P <0.05) mice. Also, mean arterial pressure (MAP, mmHg, radiotelemetry) and low frequency to high-frequency oscillation ratio (LF/HF ratio, power spectral analysis), the index of baroreflex sensitivity impairment, in response to Ang II was greater ( P <0.05, n=4) in OVX- Cyp1b1 +/+ / Alox 15 +/+ (160±3; 2.9±0.1) than in OVX- Cyp1b1 +/+ / Alox15 –/– (119±7; 2±0.1) mice. However, MAP and LF/HF ratio in response to Ang II was lower in 2ME (1.5 mg/g, every 3rd day, ip)-treated OVX- Cyp1b1 +/+ / Alox15 +/+ (108±3; 1.6±0.1) and OVX- Cyp1b1 +/+ / Alox 15 –/– (107±2; 1.6±0.1) mice (n=4). Plasma12(S)-HETE level (ELISA), and renal injury assessed by urine albumin/creatinine ratio in response to Ang II was lower in 2ME than its vehicle (dimethyl sulfoxide)-treated OVX- Cyp1b1 +/+ / Alox 15 +/+ mice (1616±30 vs 2162±55, pg/mL, and 2.7±0.3 vs 1.9±0.1; n=4, P <0.05). Ang II did not increase 12(S)-HETE or albumin/creatinine ratio in Cyp1b1 +/+ / Alo x 15 –/– mice. These data suggest that that E2-CYP1B1 generated metabolite 2ME by inhibiting A-LOX signaling protects against Ang II-induced hypertension, impaired baroreflex, and renal injury in female mice. Therefore, LOX inhibitors could be useful in the treatment of Ang II-induced hypertension and associated renal injury in females.
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Previously, we showed that Cyp1b1 gene disruption minimizes angiotensin II–induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II–induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, in Cyp1b1 +/+ mice without altering Cyp1b1 gene expression; these effects of angiotensin II were not observed in Cyp1b1 −/− mice. Angiotensin II–induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1b1 −/− or castrated Cyp1b1 +/+ mice, and restored by treatment with 6β-hydroxytestoterone. In Cyp1b1 +/+ mice, 6β-hydroxytestosterone did not alter the angiotensin II–induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1b1 +/+ or in Cyp1b1 −/− mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II–induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin–angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.
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Emerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure–lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine 473 phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine 136 and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects.
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6β-Hydroxytestosterone, a cytochrome P450 1B1-derived metabolite of testosterone, contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to angiotensin II actions on water consumption and renal function in male Cyp1b1(+/+) and Cyp1b1(-/-) mice. Castration of Cyp1b1(+/+) mice or Cyp1b1(-/-) gene disruption minimized the angiotensin II-induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-Hydroxytestosterone did not alter angiotensin II-induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality in Cyp1b1(+/+) mice, but restored these effects of angiotensin II in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice. Cyp1b1 gene disruption or castration prevented angiotensin II-induced renal fibrosis, oxidative stress, inflammation, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, and angiotensin-converting enzyme. 6β-Hydroxytestosterone did not alter angiotensin II-induced renal fibrosis, inflammation, oxidative stress, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin-converting enzyme in Cyp1b1(+/+)mice. However, in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, it restored these effects of angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with angiotensin II-induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice.
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Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-beta1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11beta-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy.
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Aldosterone administration in rats results in several cardiac alterations. Previous studies have demonstrated that proanthocyanidins, phenolic bioactive compounds, have cardioprotective effects. We studied the potential beneficial effects of the proanthocyanidin-rich almond skin extract (PASE) on the cardiac alterations induced by aldosterone-salt treatment, their effects in mineralocorticoid receptor activity and we sought to confirm proanthocyanidins as the specific component of the extract involved in the beneficial cardiac effects. Male Wistar rats received aldosterone (1 mg/Kg/day) +1% NaCl for 3 weeks. Half of the animals in each group were simultaneously treated with either PASE (100 mg/Kg/day) or spironolactone (200 mg/Kg/day). The ability of PASE to act as an antagonist of the mineralocorticoid receptor was examined using a transactivation assay. High performance liquid chromatography was used to identify and to isolate proanthocyanidins. Hypertension and diastolic dysfunction induced by aldosterone were abolished by treatment with PASE. Expression of the aldosterone mediator SGK-1, together with fibrotic, inflammatory and oxidative mediators were increased by aldosterone-salt treatment; these were reduced by PASE. Aldosterone-salt induced transcriptional activity of the mineralocorticoid receptor was reduced by PASE. HPLC confirmed proanthocyanidins as the compound responsible for the beneficial effects of PASE. The effects of PASE were comparable to those seen with the mineralocorticoid antagonist, spironolactone. The observed responses in the aldosterone-salt treated rats together with the antagonism of transactivation at the mineralocorticoid receptor by PASE provides evidence that the beneficial effect of this proanthocyanidin-rich almond skin extract is via as a mineralocorticoid receptor antagonist with proanthocyanidins identified as the compounds responsible for the beneficial effects of PASE.
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