Chou Li-Fang, Chen Ting-Wen, Yang Huang-Yu, Tian Ya-Chung, Chang Ming-Yang, Hung Cheng-Chieh, Hsu Shen-Hsing, Tsai Chung-Ying, Ko Yi-Ching, Yang Chih-Wei
Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Linkou, Taiwan.
Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
Am J Physiol Renal Physiol. 2021 May 1;320(5):F1001-F1018. doi: 10.1152/ajprenal.00640.2020. Epub 2021 Mar 29.
High-incidence regions of leptospirosis caused by spp. coincide with chronic kidney disease. This study investigated whether asymptomatic leptospirosis is an emerging culprit that predisposes to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole transcriptomic profiles were evaluated for -infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on -infected mice, were significantly increased compared with mice following infection or adenine diet alone, and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed that integrin-β- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase-signaling pathway, which were upregulated in 0.2% adenine-fed -infected mice but not in 0.2% adenine-fed mice, indicating that background subclinical infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene expression patterns with unilateral ureteric obstruction-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin-α, PDZ-binding kinase, and DNA topoisomerase II-α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease.-infected mice followed by secondary nephrotoxic injury exacerbated immune/inflammatory responses and renal fibrosis. Comparison with the murine model revealed candidates involved in the progression of renal fibrosis in chronic kidney disease (CKD). Comparative transcriptome study suggests that secondary nephrotoxic injury in -infected mice recapitulates the gene expression signatures found in CKD patients. This study indicates that secondary nephrotoxic injury may exacerbate CKD in chronic infection implicating in the progression of CKD of unknown etiology.
由 种引起的钩端螺旋体病高发地区与慢性肾脏病相吻合。本研究调查了无症状钩端螺旋体病是否是一个新出现的罪魁祸首，当叠加在继发性肾毒性损伤上时，易引发进行性慢性肾脏病。对感染 的C57/BL6小鼠进行腺嘌呤诱导的肾损伤，评估其肾脏组织学/功能和全转录组图谱。与仅感染 或仅给予腺嘌呤饮食的小鼠相比，低剂量（0.1%）腺嘌呤感染的小鼠，尤其是高剂量（0.2%）腺嘌呤喂养的叠加感染 的小鼠，肾小管间质肾损伤程度以及炎症/纤维化基因的表达显著增加，且这些发现与肾脏转录组分析一致。通路富集结果表明，整合素-β 和纤连蛋白编码基因在整合素连接激酶信号通路内有不同表达，在0.2%腺嘌呤喂养的感染 的小鼠中上调，但在0.2%腺嘌呤喂养的小鼠中未上调，这表明背景亚临床 感染确实增强了随后的继发性肾毒性肾损伤以及与继发性肾毒性钩端螺旋体病相关的潜在致病分子。将基因表达模式与单侧输尿管梗阻诱导的小鼠肾纤维化以及慢性肾脏病患者进行比较分析表明，分别在低剂量和高剂量腺嘌呤喂养的感染小鼠中鉴定出差异表达的直系同源基因，如血红蛋白-α、PDZ结合激酶和DNA拓扑异构酶II-α，揭示了与数据集中发现的相同的差异表达特征，可能作为肾脏进展加重的标志物。本研究表明，背景亚临床钩端螺旋体病在遭受不同程度的随后继发性肾毒性损伤时，可能易引发纤维化加剧，类似于进行性慢性肾脏病的病理生理过程。感染 的小鼠继发肾毒性损伤后，免疫/炎症反应和肾纤维化加剧。与小鼠模型的比较揭示了参与慢性肾脏病（CKD）肾纤维化进展的候选因素。比较转录组研究表明，感染 的小鼠中的继发性肾毒性损伤重现了CKD患者中发现的基因表达特征。本研究表明，继发性肾毒性损伤可能会加重慢性 感染中的CKD，这与病因不明的CKD进展有关。
