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The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress.

ABSTRACT: Ischemic injuries permanently affect kidney tissue and challenge cell viability, promoting inflammation and fibrogenesis. Ischemia results in nutrient deprivation, which triggers endoplasmic reticulum stress, ultimately resulting in the unfolded protein response (UPR). The aim of this study was to test whether the UPR could promote an angiogenic response independently of the HIF-1? pathway during ischemic stress in the human kidney epithelium. Glucose deprivation induced the secretion of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and angiogenin (ANG) in human kidney epithelial cells independently of HIF-1?. Glucose deprivation, but not hypoxia, triggered endoplasmic reticulum stress and activated the UPR. RNA interference-mediated inhibition of the gene encoding the kinase PERK decreased VEGFA and bFGF expression, but neither gene was affected by the inhibition of IRE1? or ATF6. Furthermore, we show that the expression of angiogenin, which inhibits protein synthesis, is regulated by both IRE1? and PERK, which could constitute a complementary function of the UPR in the repression of translation. In a rat model of acute ischemic stress, we show that the UPR is activated in parallel with VEGFA, bFGF, and ANG expression and independently of HIF-1?.

SUBMITTER: Bouvier N

PROVIDER: S-EPMC3340272 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress.

Bouvier Nicolas N Fougeray Sophie S Beaune Philippe P Thervet Eric E Pallet Nicolas N

The Journal of biological chemistry 20120308 18

Ischemic injuries permanently affect kidney tissue and challenge cell viability, promoting inflammation and fibrogenesis. Ischemia results in nutrient deprivation, which triggers endoplasmic reticulum stress, ultimately resulting in the unfolded protein response (UPR). The aim of this study was to test whether the UPR could promote an angiogenic response independently of the HIF-1α pathway during ischemic stress in the human kidney epithelium. Glucose deprivation induced the secretion of vascula ...[more]

PMID: 22403402

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Project description:BackgroundMitochondrial quality control (MQC) plays a critical role in the progression of tubulointerstitial injury in diabetic kidney disease (DKD). The mitochondrial unfolded protein response (UPRmt), which is an important MQC process, is activated to maintain mitochondrial protein homeostasis in response to mitochondrial stress. Activating transcription factor 5 (ATF5) is critical in the mammalian UPRmt via mitochondria-nuclear translocation. However, the role of ATF5 and UPRmt in tubular injury under DKD conditions is unknown.MethodsATF5 and UPRmt-related proteins including heat shock protein 60 (HSP60) and Lon peptidase 1 (LONP1), in DKD patients and db/db mice were examined by immunohistochemistry (IHC) and western blot analysis. Eight-week-old db/db mice were injected with ATF5-shRNA lentiviruses via the tail vein, and a negative lentivirus was used as a control. The mice were euthanized at 12 weeks, and dihydroethidium (DHE) and TdT-mediated dUTP nick end labeling (TUNEL) assays were performed to evaluate reactive oxygen species (ROS) production and apoptosis in kidney sections, respectively. In vitro, ATF5-siRNA, ATF5 overexpression plasmids or HSP60-siRNA were transfected into HK-2 cells to evaluate the effect of ATF5 and HSP60 on tubular injury under ambient hyperglycemic conditions. Mitochondrial superoxide (MitoSOX) staining was used to gauge mitochondrial oxidative stress levels, and the early stage of cell apoptosis was examined by Annexin V-FITC kits.ResultsIncreased ATF5, HSP60 and LONP1 expression was observed in the kidney tissue of DKD patients and db/db mice and was tightly correlated with tubular damage. The inhibition of HSP60 and LONP1, improvements in serum creatinine, tubulointerstitial fibrosis and apoptosis were observed in db/db mice treated with lentiviruses carrying ATF5 shRNA. In vitro, the expression of ATF5 was increased in HK-2 cells exposed to high glucose (HG) in a time-dependent manner, which was accompanied by the overexpression of HSP60, fibronectin (FN) and cleaved-caspase3 (C-CAS3). ATF5-siRNA transfection inhibited the expression of HSP60 and LONP1, which was accompanied by reduced oxidative stress and apoptosis in HK-2 cells exposed to sustained exogenous high glucose. ATF5 overexpression exacerbated these impairments. HSP60-siRNA transfection blocked the effect of ATF5 on HK-2 cells exposed to continuous HG treatment. Interestingly, ATF5 inhibition exacerbated mitochondrial ROS levels and apoptosis in HK-2 cells in the early period of HG intervention (6 h).ConclusionsATF5 could exert a protective effect in a very early stage but promoted tubulointerstitial injury by regulating HSP60 and the UPRmt pathway under DKD conditions, providing a potential target for the prevention of DKD progression.

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The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress.

Publications

The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress.

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