Division of Hematology and Medical Oncology.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA.
AIDS. 2020 Jun 1;34(7):989-1000. doi: 10.1097/QAD.0000000000002516.
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.
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.
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.
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.
Platelet TGF-β1 contributes to RTV-induced kidney fibrosis and dysfunction, which may be amenable to antioxidant interventions.
在接受某些基于蛋白酶抑制剂的抗逆转录病毒疗法治疗的 HIV 感染中，会发生伴有肾小管损伤和纤维化的慢性肾脏病（CKD）。其病理生理学尚不清楚。
我们假设纤维化是由血小板衍生的转化生长因子（TGF）-β1介导的，这是蛋白酶抑制剂相关 CKD 的基础。我们在接受蛋白酶抑制剂利托那韦（RTV）的小鼠中诱导了这种情况，并通过低剂量吸入一氧化碳（CO）进行干预，从而激活了红细胞 2 相关因子（Nrf2）相关的抗氧化途径。
给予野生型 C57BL/6 小鼠和缺乏血小板 TGF-β1 的小鼠每天 10mg/kg 的 RTV 或载体，共 8 周。选择的几组在 RTV 或载体注射后 4 小时暴露于 CO（250ppm）中。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 Nrf2 的信号转导。通过 KIM-1 和胱抑素 C ELISA 评估肾脏损伤和功能障碍。在 HIV 感染者中寻求临床相关性。
RTV 诱导肾小球和肾小管损伤，使尿 KIM-1 升高（P=0.004）。它增强了 TGF-β1 相关信号，同时伴有肾脏纤维化、巨噬细胞向炎症表型极化以及胱抑素 C 升高引起的肾功能障碍（P=0.008）。血小板中缺乏 TGF-β1 的小鼠对这些异常有部分保护作用。CO 抑制了 RTV 诱导的纤维化和巨噬细胞极化，同时上调了 Nrf2 和血红素加氧酶-1（HO-1）。临床上，未经治疗的 HIV 感染女性（n=17）与年龄匹配的对照组（n=19）相比，胱抑素 C 水平升高（P=0.014）。RTV 治疗的 HIV+女性的胱抑素 C 进一步升高（n=20；P=0.05），同时 HO-1 升高。
血小板 TGF-β1 有助于 RTV 诱导的肾脏纤维化和功能障碍，这可能适合抗氧化干预。
