Chronic kidney disease of unknown etiology (CKDu), manifested clinically as tubulo interstitial fibrosis, has emerged as the second major cause of chronic kidney disease (CKD) in the Indian subcontinent and various agrochemicals have been implicated in its occurance. Among the agrochemicals organochlorine pesticides particularly endosulfan is well known for its toxicity and recent residue analysis have shown its presence in the blood samples of general population. In this present study, we have investigated the consequences of endosulfan exposure at a concentration (0.01 μM) equivalent to their highest reported presence in human blood sample of some CKDu patients, to human renal proximal tubular epithelial (HK-2) cell line with regard to ROS generation and expression of profibrotic and epithelial to mesenchymal (EMT) markers in order to find out endosulfan's ability to induce profibrotic changes in renal cell. We demonstrated a significant increase in intracellular ROS generation and increased expression of TGF-β1 when cells were incubated with β-endosulfan (0.01 μM) indicating occurrence of oxidative stress and fibrotic process. Again, decreased expression of epithelial marker E-cadherin and increase in the expression of mesenchymal marker α-smooth muscle actin (α-SMA) suggest possible onset of EMT process. Pre-treatment with 5 mM concentration of anti-oxidant N-acetyl cysteine partially attenuated the above process. In conclusion, these findings suggest possible involvement of β-endosulfan in the development of CKDu through oxidative stress and profibrotic signaling.

中文翻译：

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β-硫丹介导的体外肾 (HK-2) 细胞促纤维化标志物的诱导：对未知病因慢性肾病发病机制的新见解

病因不明的慢性肾脏病 (CKDu)，临床上表现为肾小管间质纤维化，已成为印度次大陆慢性肾脏病 (CKD) 的第二大病因，其发生与多种农用化学品有关。在农用化学品中，有机氯农药尤其是硫丹以其毒性而闻名，最近的残留分析表明它存在于一般人群的血液样本中。在本研究中，我们调查了硫丹在某些 CKDu 患者的人体血液样本中所报告的最高浓度 (0.01 μM) 下暴露的后果，与人肾近端肾小管上皮 (HK-2) 细胞系的 ROS 生成和促纤维化和上皮间质 (EMT) 标记物的表达相关，以找出硫丹诱导肾细胞促纤维化变化的能力。我们证明，当细胞与 β-硫丹 (0.01 μM) 一起孵育时，细胞内 ROS 生成显着增加，TGF-β1 表达增加，表明发生了氧化应激和纤维化过程。同样，上皮标志物 E-钙粘蛋白的表达降低和间充质标志物 α-平滑肌肌动蛋白 (α-SMA) 的表达增加表明 EMT 过程可能开始。用 5 mM 浓度的抗氧化剂 N-乙酰半胱氨酸预处理部分减弱了上述过程。综上所述，