Connexin32 plays a crucial role in ROS-mediated endoplasmic reticulum stress apoptosis signaling pathway in ischemia reperfusion-induced acute kidney injury

Abstract

BackgroundIschemia–reperfusion (I/R)-induced acute kidney injury (AKI) not only prolongs the length of hospital stay, but also seriously affects the patient’s survival rate. Although our previous investigation has verified that reactive oxygen species (ROS) transferred through gap junction composed of connexin32 (Cx32) contributed to AKI, its underlying mechanisms were not fully understood and viable preventive or therapeutic regimens were still lacking. Among various mechanisms involved in organs I/R-induced injuries, endoplasmic reticulum stress (ERS)-related apoptosis is currently considered to be an important participant. Thus, in present study, we focused on the underlying mechanisms of I/R-induced AKI, and postulated that Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI.MethodsWe established renal I/R models with Cx32+/+ and Cx32−/− mice, which underwent double kidneys clamping and recanalization. ROS scavenger (N-acetylcysteine, NAC) and ERS inhibitors (4-phenyl butyric acid, 4-PBA, and tauroursodeoxycholic acid, TUDCA) were used to decrease the content of ROS and attenuate ERS activation, respectively.ResultsRenal damage was progressively exacerbated in a time-dependent manner at the reperfusion stage, that was consistent with the alternation of ERS activation, including glucose regulated protein 78 (BiP/GRP78), X box-binding protein1, and C/EBP homologous protein expression. TUDCA or 4-PBA application attenuated I/R-induced ERS activation and protected against renal tubular epithelial cells apoptosis and renal damage. Cx32 deficiency decreased ROS generation and distribution between the neighboring cells, which attenuated I/R-induced ERS activation, and improved cell apoptosis and renal damage.ConclusionCx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI. Cx32 deficiency, ROS elimination, and ERS inhibition all could protect against I/R-induced AKI.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1493-8) contains supplementary material, which is available to authorized users.

Porous Se@SiO₂ nanospheres attenuate ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) and inflammation by antioxidative stress

“…Most previous studies have demonstrated that large amounts of ROS produced by H/R in I/R-induced AKI lead to TEC damage, thus activating the inflammatory signaling pathway and triggering a cascade of inflammatory responses. 8,9,39,40 TNF-α and IL-1β are regarded as important inflammatory mediators in the early stages of acute tissue injury. 41 TNF-α and IL-1β have been confirmed to regulate the activity of helper T lymphocytes, the accumulation of neutrophils, macrophages, and lymphocytes, and as mediators of the inflammatory response.…”

“…7 However, research has provided strong evidence that oxidative stress and inflammation are major contributors to the pathogenesis of ischemic AKI. [8][9][10][11] Ischemia/reperfusion (I/R) injury can lead to the production of large amounts of reactive oxygen species (ROS) in tubular epithelial cells (TECs), thus triggering mitochondrial damage and lipid peroxidation and causing devastating cell damage. The inflammatory factors produced by TECs cause a large number of inflammatory cells to migrate and infiltrate, further aggravating renal damage, and subsequently, inflammation amplification.…”

Role of promoting inflammation of Krüppel-like factor 6 in acute kidney injury

“…Among AKI risk factors, ischemia-reperfusion (IR) is the leading as well as underlying multi-factorial pathophysiological process [5] which affecting both the renal tubular epithelium and renal microvasculature [6,7]. Many researches also have provided strong evidence that oxidative stress and inflammation are major contributors to the pathogenesis of ischemic AKI [8][9][10][11][12]. In early phase of IR, inflammation is alloantigen independent and is characterized by activation of not only classical immune cells but also resident renal cells, such as endothelial cells and tubular epithelial cells (TECs) that are extremely sensitive to oxidative stress [13].…”

The Mechanisms of the Herbal Components of CRSAS on HK-2 Cells in a Hypoxia/Reoxygenation Model Based on Network Pharmacology

“…CHOP can be activated by PERK, ATF6, and IRE1. CHOP is a proapoptotic gene, which leads to cell [22]. Additionally, activation of CHOP causing Ca 2+ released from the endoplasmic reticulum lumen aggravates ERS [14].…”