Cyclosporin A-induced hyperreninemic hypoaldosteronism. A model of adrenal resistance to angiotensin II.

Stern, Naftali; Lustig, Shlomo; Petrasek, Dan; Jensen, Greg; Eggena, Peter; Lee, D. B. N.; Tuck, M. L.

doi:10.1161/01.hyp.9.6_pt_2.iii31

Cited by 13 publications

(6 citation statements)

References 16 publications

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“…13 In addition, angiotensin II-stimulated aldosterone secretion is inhibited by PGP modulators in vitro. 14 Studies in rats 15 and humans 16 suggest that the PGP inhibitor cyclosporine A influences the renin-angiotensin-aldosterone system. These experimental results suggest that PGP might play a role in the regulation of the renin-angiotensin-aldosterone system in humans.…”

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confidence: 99%

CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by Salt

et al. 2007

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Abstract-The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: Pϭ0.05; nighttime systolic and diastolic: PϽ0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (PϽ0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation. Key Words: blood pressure Ⅲ genes Ⅲ sodium Ⅲ renin-angiotensin system Ⅲ P glycoprotein C ytochrome P450 3A (CYP3A) enzymes, which, in adults, are composed of CYP3A4 and CYP3A5, are involved in the metabolism of many drugs and endogenous substrates, such as steroids. CYP3A genes show organspecific patterns of expression, and only CYP3A5 is expressed in the human kidney. 1,2 Recent studies have found an association between the CYP3A5 gene and blood pressure (BP) in humans. [3][4][5][6] It has been hypothesized that carriers of the CYP3A5*1 allele have an enhanced renal sodium reabsorption. 3,6 The ATP-binding cassette, subfamily B, member 1 (ABCB1) or multidrug resistance 1 gene encodes the transmembrane permeability-glycoprotein (PGP), an efflux transporter expressed in the human kidney, (proximal tubules, 7 mesangium, thick limbs of Henle's loops, and collecting ducts 8 ). In mice, PGP has been shown to transport aldosterone out of the brain 9 and to play an important role in aldosterone plasma disposition. 10 This may be of importance given that intracerebroventricular injection of aldosterone in Dahl salt-sensitive rats has been shown to increase BP. 11 In Wistar rats, the increased BP resulting from intracerebroventricular injection of sodium is blocked by intracerebroventricular spironolactone injection. 12 Taken together, these experimental findings in animals point toward a possible role of PGP in centrally mediated salt-sensitive hypertension.Aldosterone may also be a physiological substrate of PGP in the hum...

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CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by Salt

et al. 2007

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“…In addition, mutations in the PGP transmembrane domains 4-6 result in loss of the recognition of steroids with the 17-OH group and the 20-keto oxygen and loss of steroidal effect (34). Hyperreninemic hypoaldosteronism resistant to ANG II stimulation has been reported, in vivo, in rats treated with the PGP substrate cyclosporin A (CSA); the zona glomerulosa cells, isolated from the same animals, also failed to respond to ANG II stimulation (23,28). In humans CSA produces hyperkalemic hyporeninism and a distal tubule defect in K ϩ excretion (16,30).…”

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confidence: 99%

Role of multidrug resistance P-glycoprotein in the secretion of aldosterone by human adrenal NCI-H295 cells

Bello‐Reuss

Ernest²,

Holland³

et al. 2000

American Journal of Physiology-Cell Physiology

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We determined the role of the multidrug resistance (MDR1) gene product, P-glycoprotein (PGP), in the secretion of aldosterone by the adrenal cell line NCI-H295. Aldosterone secretion is significantly decreased by the PGP inhibitors verapamil, cyclosporin A (CSA), PSC-833, and vinblastine. Aldosterone inhibits the efflux of the PGP substrate rhodamine 123 from NCI-H295 cells and from human mesangial cells (expressing PGP). CSA, verapamil, and the monoclonal antibody UIC2 significantly decreased the efflux of fluorescein-labeled (FL)-aldosterone microinjected into NCI-H295 cells. In MCF-7/VP cells, expressing multidrug resistance-associated protein (MRP) but not PGP, and in the parental cell line MCF7 (expressing no MRP and no PGP), the efflux of microinjected FL-aldosterone was slow. In BC19/3 cells (MCF7 cells transfected with MDR1), the efflux of FL-aldosterone was rapid and it was inhibited by verapamil, indicating that transfection with MDR1 cDNA confers the ability to transport FL-aldosterone. These results strongly indicate that PGP plays a role in the secretion of aldosterone by NCI-H295 cells and in other cells expressing MDR1, including normal adrenal cells.

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“…Telmisartan and the prodrug candesartan-cilexetil, angiotensin receptor type 1 blockers, were found to significantly inhibit Pgp activity [121, 122], which implies that important drug-drug inter-actions may occur when these drugs are combined with Pgp substrates. Studies in rats [123] and humans [124] found that the Pgp inhibitor cyclosporine A influences the renin-angiotensin-aldosterone system. Cyclosporine A belongs to the group of calcineurin inhibitors used to induce immuno-suppression after organ transplantation.…”

Section: Selected Vip Genes: Blood Pressure; Salt-sensitivity and Renmentioning

confidence: 99%

Top Three Pharmacogenomics and Personalized Medicine Applications at the Nexus of Renal Pathophysiology and Cardiovascular Medicine

Bochud¹,

Burnier²,

Guessous

2011

CPPM

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Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of 'hepatic pharmacogenes' such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.

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Cyclosporin A-induced hyperreninemic hypoaldosteronism. A model of adrenal resistance to angiotensin II.

Cited by 13 publications

References 16 publications

CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by Salt

CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by Salt

Role of multidrug resistance P-glycoprotein in the secretion of aldosterone by human adrenal NCI-H295 cells

Top Three Pharmacogenomics and Personalized Medicine Applications at the Nexus of Renal Pathophysiology and Cardiovascular Medicine

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