Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury

Abstract

We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase–3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase–3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

Autophagy in acute kidney injury

“…ER stress contributes to the development of AKI in humans and in animal models of AKI 109-111 . ER stress is known to induce autophagy in mammalian cells 111, 112 and in the kidney 113 . Tunicamycin-induced ER stress and pharmacological compound Bix that activates UPR afforded protection against renal ischemia-reperfusion (IR) injury 114, 115 and ER-induced autophagy was shown to be involved in this protection 113 .…”

“…ER stress is known to induce autophagy in mammalian cells 111, 112 and in the kidney 113 . Tunicamycin-induced ER stress and pharmacological compound Bix that activates UPR afforded protection against renal ischemia-reperfusion (IR) injury 114, 115 and ER-induced autophagy was shown to be involved in this protection 113 . Energy sensitive kinases mTORC1 and AMPK that are important components of AKI, are known to regulate autophagy 24, 26, 28, 29, 31 .…”

Astragaloside-IV Alleviates Heat-Induced Inflammation by Inhibiting Endoplasmic Reticulum Stress and Autophagy

“…Under hypoxic conditions, the increased ROS production leads to oxidative damage, possibly affecting ER homeostasis and causing ER stress [12]. ER stress elicits the unfolded protein response (UPR) to facilitate repair toward reestablishing normal ER function through the mediation of three ER-resident transducers: activating the pancreatic ER stress kinase (PERK), transcription factor 6 (ATF6), and IRE1 [13, 14]. However, the role of ER stress in heat exposure has not been completely defined.…”

“…In mammalian cells, autophagy can eliminate damaged proteins and organelles by lysosome degradation and recycle the resulting amino acids, free sugars, and fatty acids for the energy needs of the cell [15]. Under pathological conditions, autophagy is induced in response to stress conditions including cell starvation, hypoxia, oxidant injury, and heat [13]. In these cases, elevated autophagy degrades damaged material to produce metabolic substrates and to meet the bioenergy needs of the cell [16].…”

Autophagy and Tubular Cell Death in the Kidney

“…Activation of the LKB1–AMPK pathway by starvation or growth factor deprivation increases the stability of cyclin-dependent kinase inhibitor p27 kip1 and promotes cell survival through induction of autophagy, while knockdown of p27 kip1 under these conditions activates apoptosis 77 . Another important example for the crosstalk between autophagy and cell death is endoplasmic reticulum (ER) stress that induces autophagy as an adaptive response, but it can also lead to cell death by apoptosis or necrosis 78-83 . DAPK, a calcium/calmodulin regulated Ser/Thr kinase that is induced by ER stress, has been linked to both apoptosis and autophagic cell death possibly via Beclin1 84 .…”