Mathur Alpana, Rizvi Fatima, Kakkar Poonam
Herbal Research Laboratory, Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India; Babu Banarasi Das University, Lucknow, India.
Herbal Research Laboratory, Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research, CSIR-IITR, Lucknow Campus, India.
Food Chem Toxicol. 2016 Mar;89:19-31. doi: 10.1016/j.fct.2016.01.001. Epub 2016 Jan 6.
NF-E2 p45-related factor 2 (Nrf2) is a cap 'n' collar (CNC) basic region-leucine zipper (bZIP) transcription factor that imparts cellular defence against xenobiotic and oxidative stress evoked responses by inducing an array of cytoprotective genes. Essential factors that regulate Nrf2 activity and stability during analgesic nephropathy are incompletely understood. In this study, we demonstrate that acetaminophen (a classic analgesic) posit nephrotoxicity both in vitro and in vivo via PHLPP2 activation. Enhanced PHLPP2 levels down regulate p-Akt by dephosphorylating it at Ser 473 residue leading to Gsk3β activation. APAP subsided Nrf2 nuclear accumulation by activating Gsk3β which phosphorylates Fyn kinase. p-Fyn kinase translocates into the nucleus and phosphorylates Nrf2 (Tyr 568) leading to its nuclear export, ubiquitination and degradation. Therefore, poor prognosis prevails during analgesic nephrotoxicity because of the defects in Akt-1/Gsk3β/Fyn-Nrf2 signaling pathway. Morin, a bioflavonoid given as co- and pre-treatment with acetaminophen significantly prevented the toxicity induced damage by constitutively stabilizing Nrf2 nuclear retention. Diminished Nrf2 levels by APAP overdose imposed severe proximal tubular damage leading to apoptotic cell death. Morin, as a potent Nrf2 inducer accorded protection against acetaminophen induced renal damages by its molecular intervention with Akt-1/Gsk3β/Fyn kinase pathway via PHLPP2 de-activation.
核因子E2相关因子2（Nrf2）是一种帽状结构域-衣领状（CNC）碱性区域-亮氨酸拉链（bZIP）转录因子，它通过诱导一系列细胞保护基因，赋予细胞抵御外源性物质和氧化应激引起的反应的能力。在镇痛性肾病期间调节Nrf2活性和稳定性的关键因素尚未完全明确。在本研究中，我们证明对乙酰氨基酚（一种经典镇痛药）在体外和体内均可通过激活PHLPP2产生肾毒性。PHLPP2水平升高会使p-Akt在丝氨酸473残基处去磷酸化，从而下调p-Akt，导致糖原合成酶激酶3β（Gsk3β）激活。对乙酰氨基酚通过激活Gsk3β使Nrf2核内积累减少，Gsk3β会使Fyn激酶磷酸化。磷酸化的Fyn激酶转移到细胞核内并使Nrf2（酪氨酸568）磷酸化，导致其核输出、泛素化和降解。因此，由于Akt-1/Gsk3β/Fyn-Nrf2信号通路存在缺陷，在镇痛性肾毒性期间普遍存在预后不良的情况。桑色素是一种生物类黄酮，与对乙酰氨基酚联合使用或在其之前使用时，可通过持续稳定Nrf2的核内保留，显著预防毒性诱导的损伤。对乙酰氨基酚过量导致Nrf2水平降低，造成严重的近端肾小管损伤，导致细胞凋亡死亡。桑色素作为一种有效的Nrf2诱导剂，可以通过其对PHLPP2的失活作用，对Akt-1/Gsk3β/Fyn激酶途径进行分子干预，从而预防对乙酰氨基酚诱导的肾损伤。
