Abstract
Hypoxia is an important cause of acute kidney injury (AKI) in various conditions because kidneys are one of the most susceptible organs to hypoxia. In this study, we investigated whether nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) plays a role in hypoxia induced AKI in a cellular and animal model. Expression of Nox4 in cultured human renal proximal tubular epithelial cells (HK-2) was significantly increased by hypoxic stimulation. TGF-β1 was endogenously secreted by hypoxic HK-2 cells. SB4315432 (a TGF-β1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells through the Smad-dependent cell signaling pathway. Silencing of Nox4 using Nox4 siRNA and pharmacologic inhibition with GKT137831 (a specific Nox1/4 inhibitor) reduced the production of ROS and attenuated the apoptotic pathway. In addition, knockdown of Nox4 increased cell survival in hypoxic HK-2 cells and pretreatment with GKT137831 reproduce these results. This study demonstrates that hypoxia induces HK-2 cell apoptosis through a signaling pathway involving TGF-β1 via Smad pathway induction of Nox4-dependent ROS generation. In an ischemia/reperfusion rat model, pretreatment of GKT137831 attenuated ischemia/reperfusion induced acute kidney injury as indicated by preserved kidney function, attenuated renal structural damage and reduced apoptotic cells. Therapies targeting Nox4 may be effective against hypoxia-induced AKI.
Highlights
Acute kidney injury (AKI) is defined as “an abrupt reduction in kidney function” [1]
We explored the use of the HK-2 cell line as an in vitro model of hypoxia-induced kidney injury
HK-2 cell apoptosis driven by hypoxia-induced oxidative stress involves the Transforming growth factor (TGF)-β/Smad/ Nox4 signaling pathway in this study
Summary
Acute kidney injury (AKI) is defined as “an abrupt (within 48 hours) reduction in kidney function” [1]. AKI can progress to chronic kidney disease (CKD) and increase in-hospital mortality four-fold [2]. Hypoxia leads to energy shortages in tissues, and induces changes in intracellular signaling systems and gene expression. ROS play an important role in maintaining a normal intracellular signaling system in a stable state under normal conditions but the amount of ROS increases markedly in the pathologic state, acting as a crucial cause of AKI. Because among seven Nox families, Nox is the most abundant in the human kidney, changes of Nox expression in hypoxia are predicted to affect the progression of AKI by altering the intracellular ROS level in the kidney. Few studies have investigated the role of Nox in hypoxia induced AKI [12,13,14]. We investigated the role of Nox and the benefits of Nox inhibition in hypoxia induced AKI
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