HIV protease inhibitor ritonavir induces renal fibrosis and dysfunction: role of platelet-derived TGF-β1 and intervention via antioxidant pathways.
HIV protease inhibitor ritonavir induces renal fibrosis and dysfunction: role of platelet-derived TGF-β1 and intervention via antioxidant pathways.
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HIV 蛋白酶抑制剂利托那韦诱导肾纤维化和功能障碍：血小板衍生的 TGF-β1 的作用和通过抗氧化途径的干预。
DOI：
10.1097/qad.0000000000002516
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Ahamed,Jasimuddin
中科院分区：
文献类型：
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作者：
Laurence,Jeffrey;Elhadad,Sonia;Gostynska,Sandra;Yu,Zhongxin;Terry,Hunter;Varshney,Rohan;Fung,Kar-Ming;Choi,MaryE;Ahamed,Jasimuddin
目的：慢性肾脏病（CKD）伴肾小管损伤和纤维化发生在HIV感染者中，使用某些蛋白酶激活剂为基础的抗逆转录病毒治疗。病理生理学尚不清楚。设计：我们假设由血小板衍生转化生长因子（TGF）-β1介导的纤维化是蛋白酶促生长因子相关CKD的基础。我们在暴露于蛋白酶抑制剂利托那韦（RTV）的小鼠中诱导这种情况，并以低剂量吸入一氧化碳（CO）进行干预，激活红细胞2相关因子（Nrf 2）相关的抗氧化pathways.Methods：野生型C57 BL/6小鼠和血小板TGF-β1缺陷小鼠每天给予RTV（10 mg/kg）或溶媒，持续8周。选择组暴露于CO（250 ppm）4小时后，RTV或车辆注射。通过组织学、免疫荧光和流式细胞术检查肾脏疾病、纤维化以及基于TGF-β1和基于Nrf 2的信号传导。采用KIM-1和半胱氨酸蛋白酶抑制剂C ELISA检测肾损害和功能障碍。HIV感染者中寻找临床相关性。结果：RTV引起肾小球和肾小管损伤，尿KIM-1升高（P= 0.004）。它增强了TGF-β1相关的信号传导，伴有肾纤维化、巨噬细胞极化为炎性表型和肾功能不全伴胱抑素C升高（P= 0.008）。血小板中缺乏TGF-β1的小鼠部分免受这些异常的影响。CO抑制RTV诱导的纤维化和巨噬细胞极化与上调Nrf 2和血红素加氧酶-1（HO-1）。在临床上，HIV感染与未治疗女性（n= 17）与年龄匹配的对照组（n= 19; P= 0.014）的胱抑素C水平升高相关。HIV感染者血清胱抑素C水平进一步升高（n= 20; P= 0.05），HO-1水平也相应升高。结论：血小板TGF-β1参与了HIV感染者肾纤维化和肾功能障碍的发生，抗氧化干预可能是HIV感染者肾纤维化和肾功能障碍的重要原因。
Objective:Chronic kidney disease (CKD) with tubular injury and fibrosis occurs in HIV infection treated with certain protease inhibitor-based antiretroviral therapies. The pathophysiology is unclear.Design:We hypothesized that fibrosis, mediated by platelet-derived transforming growth factor (TGF)-β1, underlies protease inhibitor-associated CKD. We induced this in mice exposed to the protease inhibitor ritonavir (RTV), and intervened with low-dose inhaled carbon monoxide (CO), activating erythroid 2-related factor (Nrf2)-associated antioxidant pathways.Methods:Wild-type C57BL/6 mice and mice deficient in platelet TGF-β1, were given RTV (10 mg/kg) or vehicle daily for 8 weeks. Select groups were exposed to CO (250 ppm) for 4 h after RTV or vehicle injection. Renal disorder, fibrosis, and TGF-β1-based and Nrf2-based signaling were examined by histology, immunofluorescence, and flow cytometry. Renal damage and dysfunction were assessed by KIM-1 and cystatin C ELISAs. Clinical correlations were sought among HIV-infected individuals.Results:RTV-induced glomerular and tubular injury, elevating urinary KIM-1 (P= 0.004). It enhanced TGF-β1-related signaling, accompanied by kidney fibrosis, macrophage polarization to an inflammatory phenotype, and renal dysfunction with cystatin C elevation (P= 0.008). Mice lacking TGF-β1 in platelets were partially protected from these abnormalities. CO inhibited RTV-induced fibrosis and macrophage polarization in association with upregulation of Nrf2 and heme oxygenase-1 (HO-1). Clinically, HIV infection correlated with elevated cystatin C levels in untreated women (n= 17) vs. age-matched controls (n= 19; P= 0.014). RTV-treated HIV+ women had further increases in cystatin C (n= 20; P= 0.05), with parallel elevation of HO-1.Conclusion:Platelet TGF-β1 contributes to RTV-induced kidney fibrosis and dysfunction, which may be amenable to antioxidant interventions.
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发表时间：
1980-12
期刊：
The Journal of pharmacology and experimental therapeutics
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作者：
J. C. Yeung;T. Rudy
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J. C. Yeung;T. Rudy