小鼠肾脏细小病毒对慢性肾脏病化疗药物动力学和腺嘌呤模型的影响。

IF 1.3 4区 农林科学 Q2 VETERINARY SCIENCES Comparative medicine Pub Date : 2023-04-01 Epub Date: 2023-03-27 DOI:10.30802/AALAS-CM-22-000084
Amanda C Ritter, Rodolfo Ricart J Arbona, Robert S Livingston, Sébastien Monette, Neil S Lipman
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引用次数: 0

摘要

小鼠肾细小病毒(MKPV)在免疫功能严重受损的小鼠中引起包涵体肾病,在免疫功能正常的小鼠中导致肾间质炎症。在这里,我们试图确定MKPV对依赖于肾功能的临床前小鼠模型的影响。为了评估MKPV感染对2种经肾排泄的化疗药物甲氨蝶呤和来那度胺的药代动力学的影响,我们测量了MKPV感染或未感染的免疫缺陷NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG)和免疫活性C57BL/6NCrl(B6)雌性小鼠血液和尿液中的药物浓度。来那度胺的血浆药代动力学没有观察到差异。然而,甲氨蝶呤的AUC在未感染的NSG小鼠中比感染的NSG小鼠高1.5倍,在感染的B6小鼠中比未感染的B6鼠高1.9倍,在未感染NSG小鼠的AUC比未感染B6鼠高4.3倍。MKPV感染对两种药物的肾清除率均无显著影响。为了评估MKPV感染对慢性肾脏疾病腺嘌呤饮食模型的影响,MKPV感染和未感染的B6雌性小鼠喂食0.2%腺嘌呤饮食,并在8周内评估疾病的临床和组织病理学特征。MKPV感染不会显著改变尿液化学结果、血象结果或BUN、肌酸酐或对称二甲基精氨酸的血清浓度。然而,感染确实会影响组织学结果。与未感染的小鼠相比,MKPV感染的小鼠在饮食摄入4周和8周后有更多的间质淋巴浆细胞浸润,在第8周时有更少的间质纤维化。感染和未感染小鼠的巨噬细胞浸润和肾小管损伤相似。这些发现表明,MKPV感染对2种化疗药物的肾脏排泄和肾功能的血清生物标志物的影响最小。然而,感染显著影响了慢性肾脏疾病腺嘌呤饮食模型的两个组织学特征。无MKPV的小鼠在评估肾脏组织学作为实验结果的研究中至关重要。
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Effects of Mouse Kidney Parvovirus on Pharmacokinetics of Chemotherapeutics and the Adenine Model of Chronic Kidney Disease.

Mouse kidney parvovirus (MKPV) causes inclusion body nephropathy in severely immunocompromised mice and renal interstitial inflammation in immunocompetent mice. Here we sought to determine the effects of MKPV on pre-clinical murine models that depend on renal function. To assess the effects of MKPV infection on the pharmacokinetics of 2 renally excreted chemotherapeutic agents, methotrexate and lenalidomide, we measured drug concentrations in the blood and urine of MKPV-infected or uninfected immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) and immunocompetent C57BL/6NCrl (B6) female mice. No differences in plasma pharmacokinetics were observed for lenalidomide. However, the AUC of methotrexate was 1.5-fold higher in uninfected NSG mice compared with infected NSG mice, 1.9-fold higher in infected B6 mice compared with uninfected B6 mice, and 4.3-fold higher in uninfected NSG mice compared with uninfected B6 mice. MKPV infection did not significantly affect the renal clearance of either drug. To assess effects of MKPV infection on the adenine diet model of chronic kidney disease, MKPV-infected and uninfected B6 female mice were fed a 0.2% adenine diet, and clinical and histopathologic features of disease were assessed over 8 wk. MKPV infection did not significantly alter urine chemistry results, hemogram findings, or serum concentrations of BUN, creatinine, or symmetric dimethylarginine. However, infection did influence histologic outcomes. As compared with uninfected mice, MKPV-infected mice had more interstitial lymphoplasmacytic infiltrates after 4 and 8 wk of diet consumption and less interstitial fibrosis at week 8. Macrophage infiltrates and renal tubular injury were similar between in infected and uninfected mice. These findings indicate that MKPV infection had minimal effects on the renal excretion of 2 chemotherapeutics and on serum biomarkers of renal function. However, infection significantly influenced two histologic features of the adenine diet model of chronic renal disease. MKPV-free mice are critically important in studies evaluating renal histology as an experimental outcome.

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来源期刊
Comparative medicine
Comparative medicine 医学-动物学
CiteScore
1.90
自引率
0.00%
发文量
71
审稿时长
6-12 weeks
期刊介绍: Comparative Medicine (CM), an international journal of comparative and experimental medicine, is the leading English-language publication in the field and is ranked by the Science Citation Index in the upper third of all scientific journals. The mission of CM is to disseminate high-quality, peer-reviewed information that expands biomedical knowledge and promotes human and animal health through the study of laboratory animal disease, animal models of disease, and basic biologic mechanisms related to disease in people and animals.
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