PbAc Triggers Oxidation and Apoptosis via the PKA Pathway in NRK-52E Cells
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PbAc Triggers Oxidation and Apoptosis via the PKA Pathway in NRK-52E Cells Duanya Liu 1 & Jun Yu 1 & Jie Xie 1 & Zhaoyu Zhang 1 & Caoli Tang 1 & Tianmei Yu 1 & Shouni Chen 1 & Zhidan Hong 2 & Chunhong Wang 1 Received: 20 July 2020 / Accepted: 6 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract This study aimed to investigate the mechanism of the lead exposure-induced oxidative stress and apoptosis of renal tubular epithelial cells. We explored the effects of lead acetate (PbAc) on the oxidation and apoptosis of renal proximal tubular cells (NRK-52E) through in vitro experiments. Results showed that PbAc induced dose-dependent reactive oxygen species (ROS) accumulation in NRK-52E cells, and the activities of superoxide dismutase (SOD) and glutathione (GSH) decreased, whereas the malondialdehyde (MDA) content increased. Under the exposure of 40 and 80 μM PbAc, the mRNA level of B cell lymphoma-2 (Bcl-2) in the cells decreased, the mRNA levels of Bcl-2-associated X protein (Bax) and caspase-3 increased, and apoptosis was obvious. Furthermore, the nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) activity was enhanced by PbAc in a dose-dependent manner. The mRNA levels of protein kinase A (PKA) were upregulated by PbAc. H-89, a PKA inhibitor, suppressed PKA activation, ROS accumulation, and Nox4 activity in NRK-52E cells. Our results indicated that PbAc potentially stimulated oxidative stress and apoptosis in NRK-52E cells by increasing Nox4-dependent ROS production via the PKA signaling pathway. Keywords PbAc . Tubular cells . Oxidative stress . PKA . Nox4
Introduction Lead (Pb) exerts toxic effects on several organ systems, but its effects on the kidney are the most insidious because this organ plays an important role in the excretion of Pb in the body [1]. Pb exposure usually induces nephrotoxicity by regulating oxidative stress, adverse reactions, and apoptosis [2]. Reactive oxygen species (ROS) or free radicals, such as superoxide ion (O2·–), hydroxyl radical (OH−), and nitrogen oxide (NO), have a pivotal role in Pb-induced nephrotoxicity [3]. However, the mechanism by which Pb induces free radical production in the kidney is still not clearly understood. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) transfers electrons and reduces molecular oxygen to generate O2·– , which is considered an active producer
* Chunhong Wang [email protected] 1
Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan 430071, People’s Republic of China
2
Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, People’s Republic of China
of ROS [4]. Nox is one of the most important enzymes that produce ROS in the kidney. Five subtypes of oxidases generate ROS: Nox1, Nox2, Nox3, Nox4, and Nox5. Nox4 is highly expressed in the kidney, especially in tubular cells [5]. Importantly, recent studies have shown that Nox4 is involved in the pathologic processes of many kidney diseases, such as diabetic nep
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