Monocrotaline-induced renal lesions

Kurozumi, Takeshi; Tanaka, Kenzö; Kido, Masamitsu; Shoyama, Yukihiro

doi:10.1016/0014-4800(83)90066-7

Cited by 17 publications

(11 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast to a previous report that MCT induces nephrotoxicity, as demonstrated by necrotic changes in the glomeruli and hemosiderin granules in tubular epithelial cells, as well as focal endothelial cell detachment [31,32] , we found that MCT caused apoptosis of renal tubular cells in WT mice ( Figure 2B). This disparity might be due to differences in species, route of MCT administration or sampling time.…”

Section: Discussioncontrasting

confidence: 54%

Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice

Yao

Gong

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Monocrotaline (MCT) in plants of the genus Crotalaria induces significant toxicity in multiple organs including the liver, lung and kidney. Metabolic activation of MCT is required for MCT-induced toxicity. In this study, we attempted to determine whether the toxicity of MCT in kidney was a consequence of the metabolic activation of MCT in the liver. Methods: Liver-specific cytochrome P450 reductase-null (Null) mice, wild-type (WT) mice and CYP3A inhibitor ketoconazole-pretreated WT (KET-WT) mice were examined. The mice were injected with MCT (300, 400, or 500 mg/kg, ip), and hepatotoxicity and nephrotoxicity were examined 24 h after MCT treatment. The levels of MCT and its metabolites in the blood, liver, lung, kidney and bile were determined using LC-MS analysis. Results: Treatment of WT mice with MCT increased the serum levels of alanine aminotransferase, hyaluronic acid, urea nitrogen and creatinine in a dose-dependent manner. Histological examination revealed that MCT (500 mg/kg) caused severe liver injury and moderate kidney injury. In contrast, these pathological abnormalities were absent in Null and KET-WT mice. After injection of MCT (400 and 500 mg/kg), the plasma, liver, kidney and lung of WT mice had significantly lower MCT levels and much higher N-oxide metabolites contents in compared with those of Null and KET-WT mice. Furthermore, WT mice had considerably higher levels of tissue-bound pyrroles and bile GSH-conjugated MCT metabolites compared with Null and KET-WT mice. Conclusion: Cytochrome P450s in mouse liver play a major role in the metabolic activation of MCT and thus contribute to MCT-induced renal toxicity.

show abstract

Section: Discussioncontrasting

confidence: 54%

Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice

Yao

Gong

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…Another organ sensitive to the effect of monocrotaline is the kidney, and previous studies have used monocrotaline injection as a model of renal injury (18). Although this study was not designed to evaluate kidney function, we found that monocrotaline resulted in reduced kidney uptake of 99m Tc-AM-L by about 50%.…”

Section: Discussionmentioning

confidence: 54%

Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Dupuis

Harel

et al. 2009

J Nucl Med

View full text Add to dashboard Cite

No test currently exists for molecular imaging of pulmonary arterial hypertension (PAH). Adrenomedullin is a vasodilator peptide predominantly cleared by pulmonary endothelial receptors. We developed a linear adrenomedullin derivative radiolabeled with 99m Tc ( 99m Tc-AM-L) for imaging of pulmonary circulation and tested its capacity to detect anomalies of pulmonary circulation caused by PAH. Methods: PAH was induced by monocrotaline in rats and compared with controls. After 5 wk, 99m Tc-AM-L was injected intravenously. Plasma kinetics were measured, lung activity was determined in vivo after 30 min using a nuclear camera, and lung activity was determined ex vivo in explanted lungs. Expression of adrenomedullin receptors was measured in lung homogenates. Results: The plasma levels of 99m Tc-AM-L significantly increased in PAH by approximately 2-fold. Uptake by the lungs was homogeneous but greatly reduced in PAH by about 70%. In vivo retention was 14% 6 1% (mean 6 SD) of the injected dose in controls and 4% 6 1% in PAH (P , 0.0001). A similar reduction was measured ex vivo (6.0 6 1.6 percentage injected dose per gram [%ID/g] vs. 0.95 6 0.21 %ID/g, P , 0.0001). The expression of the heterodimeric component of the adrenomedullin receptor, receptor activity modifying protein 2, was also greatly reduced in PAH lungs (P , 0.001). Interestingly, right ventricular uptake of 99m Tc-AM-L was increased by PAH (P 5 0.02) and correlated with the degree of right ventricular hypertrophy (r 5 0.83, P 5 0.001). Conclusion: Pulmonary uptake of 99m Tc-AM-L is greatly reduced in monocrotaline-induced PAH. This novel molecular imaging agent may be useful in the diagnosis and follow-up of pulmonary vascular disorders. No clinically available test currently exists that can provide both anatomic and functional information on the status of pulmonary circulation. Pulmonary arterial hypertension (PAH) is a disorder characterized by endothelial dysfunction, with intimal and vascular smooth muscle proliferation leading to gradual obliteration of pulmonary arterioles (1). PAH is screened by transthoracic Doppler echocardiography, with the estimation of pulmonary artery systolic pressure obtained using the tricuspid valve regurgitant jet. Although this approach correlates with hemodynamically measured pulmonary pressure, it does not provide direct information on the biology of pulmonary circulation and may miss the early presence of pulmonary vascular disease (1). The recent availability of oral therapies for PAH such as endothelin receptor antagonists and phophodiesterase inhibitors advocates for earlier diagnosis of this condition and treatment of subjects in functional class II (1). There is, therefore, a clinical need for novel diagnostic approaches toward pulmonary vascular disease that could provide an earlier and more precise diagnosis.Adrenomedullin is a vasodilator peptide produced by the vascular endothelium. When injected intravenously, adrenomedullin is predominantly cleared by pulmonary circulation by specific adrenomedullin rec...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Indeed, the prevention of MCTinduced vascular damage in the lung unmasked profound renal toxicity, which had been previously recognized in the reports that first characterized the toxicity of MCT. 23,24 This additional toxic effect of MCT clearly represents a significant limitation for studies of long-term survival after lung-specific therapy of PAH in this model.The efficacy of nontransduced ELPCs in the prevention of PAH in this study are in contrast with a recent report using human umbilical cord progenitor cells injected into immunodeficient rats, 25 in which significant prevention of MCTinduced PAH was seen only with adrenomedullin-transfected cells, with little or no benefit using ELPCs alone. This discrepancy may be related to differences in the source of progenitor cells (ie, cord blood versus bone marrow) or to species-specific factors that may limit the regenerative effects of human cells in the rat model.…”

mentioning

confidence: 99%

Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow–Derived Endothelial-Like Progenitor Cells

Zhao

Courtman

Deng

et al. 2005

Circulation Research

431

376

View full text Add to dashboard Cite

Abstract-Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascularresistance caused by narrowing and loss of pulmonary microvasculature, which in its late stages becomes refractory to traditional therapies. We hypothesized that bone marrow-derived endothelial progenitor cells (EPCs), which normally function to repair and regenerate blood vessels, would restore pulmonary hemodynamics and increase microvascular perfusion in the rat monocrotaline (MCT) model of PAH. Mononuclear cells were isolated from the bone marrow of syngeneic Fisher-344 rats by Ficoll gradient centrifugation and cultured for 7 to 10 days in endothelial growth medium. Fluorescently labeled endothelial-like progenitor cells (ELPCs) engrafted at the level of the distal pulmonary arterioles and incorporated into the endothelial lining in the MCT-injured lung. The administration of ELPCs 3 days after MCT nearly completely prevented the increase in right ventricular systolic pressure seen at 3 weeks with MCT alone (31.5Ϯ0.95 versus 48Ϯ3 mm Hg, respectively; PϽ0.001), whereas injection of skin fibroblasts had no protective effect (50.9Ϯ5.4 mm Hg). Delayed administration of progenitor cells 3 weeks after MCT prevented the further progression of PAH 2 weeks later (ie, 5 weeks after MCT), whereas only animals receiving ELPCs transduced with human endothelial NO-synthase (eNOS) exhibited significant reversal of established disease at day 35 (31Ϯ2 mm Hg, PϽ0.005) compared with day 21 (50Ϯ3 mm Hg). Fluorescent microangiography revealed widespread occlusion of pulmonary precapillary arterioles 3 weeks after MCT, whereas arteriolar-capillary continuity and microvascular architecture was preserved with the administration of syngeneic ELPCs. Moreover, the delivery of ELPCs to rats with established PAH resulted in marked improvement in survival, which was greatest in the group receiving eNOS-transduced cells. We conclude that bone marrow-derived ELPCs can engraft and repair the MCT-damaged lung, restoring microvasculature structure and function. Therefore, the regeneration of lung vascular endothelium by injection of progenitor cells may represent a novel treatment paradigm for patients with PAH. ( Key Words: progenitor cells Ⅲ pulmonary hypertension Ⅲ endothelium Ⅲ endothelial nitric oxide synthase P ulmonary arterial hypertension (PAH) is a devastating disease that in its most severe form, idiopathic PAH, leads to progressive debilitation and death, often within 2 to 3 years after its initial diagnosis. 1 Despite significant advances in the therapy of PAH during the last decade, the prognosis remains poor. Although the genetic basis for some patients with familial PAH has been elucidated, 2-4 how these mutations are causally linked to the development of PAH remains unclear. 5,6 Evidence from experimental models as well as lung specimens from patients with PAH underlines the importance of microvascular occlusion in the pathogenesis of this disease, 7 especially in its advanced stages; however, the precise mechanisms...

show abstract

Monocrotaline-induced renal lesions

Cited by 17 publications

References 9 publications

Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice

Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice

Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow–Derived Endothelial-Like Progenitor Cells

Contact Info

Product

Resources

About