Mechanisms of FK 506–Induced Hypertension in the Rat

Takeda, Yoshiyu; Miyamori, Isamu; Furukawa, Kazuhiro; Inaba, Shin-ichi; Mabuchi, Hiroshi

doi:10.1161/01.hyp.33.1.130

Cited by 61 publications

(66 citation statements)

References 54 publications

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“…Interestingly, it was this dose in contrast to a higher dose that inhibited atherosclerotic plaque development and progression in Apoe -/-mice (33,34). Moreover, high doses of FK506 (>10 fold of those used in our study) caused systemic hypertension and transplant vasculopathy in animal models, presumably mediated by a paradoxical decrease in eNOS and increase in endothelin production (67). In contrast, the low-dose FK506 used in our studies did not induce systemic hypertension, even after a 3-week treatment.…”

Section: Discussioncontrasting

confidence: 53%

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

Spiekerkoetter

Tian²,

Cai³

et al. 2013

J. Clin. Invest.

367

370

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Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH. IntroductionIdiopathic pulmonary arterial hypertension (IPAH) is a rare disorder thought to develop following a genetic and/or environmental insult that triggers endothelial cell (EC) apoptosis, loss of distal vessels, and occlusive vascular remodeling (1). These pathological changes increase resistance to pulmonary flow and cause progressive right heart failure. Current therapies mainly include drugs with vasodilatory properties that improve cardiopulmonary function (2). However, the obliterative vascular pathology usually continues to progress (3), leaving heart-lung transplantation as the only option for many patients. Therefore, new approaches are needed that focus on activating cellular mechanisms to reverse vascular remodeling. One strategy could be to improve function of the bone morphogenetic protein receptor-2 (BMPR2) signaling pathway. Germline mutations causing loss of BMPR2 function are found in >80% of familial and approximately 20% of sporadic cases of IPAH (4, 5). Acquired somatic chromosomal abnormalities in the BMPR2 signaling pathway have also been described (6). The low penetrance of pulmonary arterial hypertension (PAH) found in nonaffected family members with a BMPR2 mutation has been attributed to a higher level of

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Section: Discussioncontrasting

confidence: 53%

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

Spiekerkoetter

Tian²,

Cai³

et al. 2013

J. Clin. Invest.

367

370

View full text Add to dashboard Cite

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“…Our result is in accordance with the finding of Takeda et al (4). They reported that administration of FK506 (5 mg / kg per day, by gavage) for 4 weeks results in hypertension in rats (4).…”

Section: Discussionsupporting

confidence: 94%

“…In rats, after 21-day treatment with FK506, hypertension is not induced, but 30 day-treatment causes hypertension (3,4). FK506-induced hypertension is due to the increase in endothelin-1 synthesis in the vasculature (4).…”

Section: Introductionmentioning

confidence: 99%

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Short-Term and Long-Term FK506 Treatment Alters the Vascular Reactivity of Renal and Mesenteric Vascular Beds

2006

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Abstract. The aims of this study were to investigate the role of endothelin-1 in FK506-induced hypertension and vascular dysfunction of rats treated with the drug for 8 (short-term) or 30 (long-term) days and to measure malondialdehyde levels in the kidneys. Kidney and mesentery of rats were perfused. In the short-term treated groups, there was no significant change in systolic blood pressure. The response to noradrenaline only in renal vascular beds was significantly increased by FK506 and this increase was prevented by Bosentan. FK506 had no significant effect on sodium nitroprusside-induced vasodilation in comparison with solvent in both vascular beds. Bosentan failed to prevent these responses. In the long-term treated groups, at the end of the treatment with FK506, there was a significant increase in blood pressure, but no change in the response to noradrenaline in either kidneys or mesentery. The increase in blood pressure was prevented by bosentan treatment. FK506 increased malondialdehyde levels in the kidneys of the rats from only the long-term treated groups. Bosentan did not change this increase. Our results indicated that endothelin-1 plays a key role in the FK506-induced change in vascular reactivity to noradrenaline in renal vascular beds and drug-induced hypertension in the rats. There was no relationship between oxidative stress and FK506-induced hypertension.

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“…These immunosuppressors could also cause endothelial dysfunction, acting on the NO production within proximal cells. The reduced endothelial NO production in renal transplants due to these immunosuppressors, may cause hypertension and contribute to the high risk of developing premature atherosclerosis observed in patients with renal transplants (27,28).…”

Section: Discussionmentioning

confidence: 99%

The Arginine-Creatine Pathway is Disturbed in Children and Adolescents With Renal Transplants

Andrade¹,

Rodríguez‐Soriano²,

Prieto³

et al. 2008

Pediatr Res

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Cardiovascular disease is an important cause of morbidity in recipients of renal transplants. The aim of the present study was to analyze the status of the arginine-creatine pathway in such patients, given the relationship between the arginine metabolism and both renal function and the methionine-homocysteine cycle. Twentynine children and adolescents (median age 13, range 6 -18 years), who had received a renal allograft 14.5-82.0 months before, were recruited for the study. On immunosuppressive therapy, all patients evidenced an adequate level of renal function. Plasma concentrations of homocysteine and glycine were significantly higher, whereas urinary excretions of guanidinoacetate and creatine were significantly lower than controls. Urinary excretions of guanidinoacetate and creatine correlated positively with creatinine clearance. Urinary excretion of creatine was negatively correlated with plasma concentration of homocysteine. The demonstration of disturbances in the arginine-creatine pathway in patients with well-functioning renal transplants and in absence of chronic renal failure represents a novel finding. We speculate that the low urinary excretion of guanidinoacetate and creatine is probably related to the nephrotoxic effect of immunosuppressive therapy and to defective methylation associated with the presence of hyperhomocysteinemia. (Pediatr Res 64: [218][219][220][221][222] 2008)

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Mechanisms of FK 506–Induced Hypertension in the Rat

Cited by 61 publications

References 54 publications

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

Short-Term and Long-Term FK506 Treatment Alters the Vascular Reactivity of Renal and Mesenteric Vascular Beds

The Arginine-Creatine Pathway is Disturbed in Children and Adolescents With Renal Transplants

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