Endoplasmic reticulum (ER) degradation via autophagy is a process that maintains ER homeostasis when cells are in a state of stress and is associated with many diseases; however, the role of hypoxia inducible factor-1α (HIF-1α)-mediated ER degradation and the related regulatory pathway in acute kidney injury (AKI) still needs to be further established.
Results:
In the present study, an in vivo AKI model was induced in mice via the ischemia–reperfusion (IR) method. The results revealed that HIF-1α and BNIP3 were increased, and autophagy and ER degradation were activated in the kidneys of AKI mice, whereas HIF-1α knockout significantly inhibited BNIP3, autophagy and ER degradation, accompanied by aggravated kidney injury. Overexpression of HIF-1α in vitro significantly increased BNIP3, autophagy and ER degradation, whereas inhibition of BNIP3 significantly reversed the effects of HIF-1α. In addition, the in vitro inhibition of autophagy with chloroquine significantly reversed the effects of HIF-1α on cell apoptosis. Moreover, selectively overexpressing BNIP3 on the ER membrane significantly increased ER degradation via autophagy and decreased cell apoptosis in vitro.
Innovation and Conclusion:
These data indicate that HIF-1α/BNIP3-mediated ER degradation via autophagy in tubular cells protects against IR-induced AKI. Antioxid. Redox Signal. 42, 212–227.
BoziL, TakanoA, CamposJC, et al.Endoplasmic reticulum stress impairs cardiomyocyte contractility through JNK-dependent upregulation of BNIP3. Int J Cardiol, 2018; 272:194–201.
5.
BruzzeseL, LumetG, VairoD, et al.Hypoxic preconditioning in renal ischaemia-reperfusion injury: A review in pre-clinical models. Clin Sci, 2021; 135(23):2607–2618.
6.
ChaanineAH, GordonRE, KohlbrennerE, et al.Potential role of BNIP3 in cardiac remodeling, myocardial stiffness, and endoplasmic reticulum: Mitochondrial calcium homeostasis in diastolic and systolic heart failure. Circ Heart Fail, 2013; 6(3):572–583.
7.
ChenX, ShenWB, YangP, et al.High glucose inhibits neural stem cell differentiation through oxidative stress and endoplasmic reticulum stress. Stem Cells Dev, 2018; 27(11):745–755.
8.
ChinoH, HattaT, NatsumeT, et al.Intrinsically disordered protein TEX264 mediates ER-phagy. Mol Cell, 2019; 74(5):909–921.e6.
9.
ChinoH, MizushimaN. ER-Phagy: Quality control and turnover of endoplasmic reticulum. Trends Cell Biol, 2020; 30(5):384–398.
10.
DandekarA, MendezR, ZhangK. Cross talk between ER stress, oxidative stress, and inflammation in health and disease. Methods Mol Biol, 2015; 1292:205–214.
11.
DiwanA, KrenzM, SyedFM, et al.Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of BNIP3 restrains postinfarction remodeling in mice. J Clin Invest, 2007; 117(10):2825–2833.
12.
ErkanM, KleeffJ, EspositoI, et al.Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene, 2005; 24(27):4421–4432.
13.
FuZJ, WangZY, XuL, et al.HIF-1alpha-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury. Redox Biol, 2020; 36:101671.
14.
FumagalliF, NoackJ, BergmannTJ, et al.Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat Cell Biol, 2016; 18(11):1173–1184.
15.
Hamacher-BradyA, BradyNR, LogueSE, et al.Response to myocardial ischemia/reperfusion injury involves BNIP3 and autophagy. Cell Death Differ, 2007; 14(1):146–157.
16.
HannaRA, QuinsayMN, OrogoAM, et al.Microtubule-associated protein 1 light chain 3 (LC3) interacts with BNIP3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem, 2012; 287(23):19094–19104.
17.
HubnerCA, DikicI. ER-phagy and human diseases. Cell Death Differ, 2020; 27(3):833–842.
18.
JiangM, LiuK, LuoJ, et al.Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury. Am J Pathol, 2010; 176(3):1181–1192.
19.
KaleJ, OsterlundEJ, AndrewsDW. BCL-2 family proteins: Changing partners in the dance towards death. Cell Death Differ, 2018; 25(1):65–80.
20.
KangR, ZehHJ, LotzeMT, et al.The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ, 2011; 18(4):571–580.
KimKH, LeeMS. Autophagy–a key player in cellular and body metabolism. Nat Rev Endocrinol, 2014; 10(6):322–337.
23.
LiR, XinT, LiD, et al.Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: The role of the ERK-CREB pathway and BNIP3-mediated mitophagy. Redox Biol, 2018; 18:229–243.
24.
LinSL, ChenRH, ChenYM, et al.Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol, 2005; 16(9):2702–2713.
25.
LinQ, LiS, JiangN, et al.Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy. Autophagy, 2021; 17(10):2975–2990.
26.
LoiM, FregnoI, GuerraC, et al.Eat it right: ER-phagy and recovER-phagy. Biochem Soc Trans, 2018; 46(3):699–706.
27.
MalekM, NematbakhshM. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev, 2015; 4(2):20–27.
28.
MatsumotoM, MakinoY, TanakaT, et al.Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J Am Soc Nephrol, 2003; 14(7):1825–1832.
29.
MehtaRL, BurdmannEA, CerdaJ, et al.Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: A multinational cross-sectional study. Lancet, 2016; 387(10032):2017–2025.
30.
NeyPA. Mitochondrial autophagy: Origins, significance, and role of BNIP3 and NIX. Biochim Biophys Acta, 2015; 1853(10 Pt B):2775–2783.
31.
OakesSA, PapaFR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol, 2015; 10:173–194.
32.
OmuraT, SiekevitzP, PaladeGE. Turnover of constituents of the endoplasmic reticulum membranes of rat hepatocytes. J Biol Chem, 1967; 242(10):2389–2396.
33.
O’SullivanTE, JohnsonLR, KangHH, et al.BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory. Immunity, 2015; 43(2):331–342.
Periyasamy-ThandavanS, JiangM, WeiQ, et al.Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. Kidney Int, 2008; 74(5):631–640.
36.
RashidHO, YadavRK, KimHR, et al.ER stress: Autophagy induction, inhibition and selection. Autophagy, 2015; 11(11):1956–1977.
37.
RosenbergerC, RosenS, ShinaA, et al.Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney. Nephrol Dial Transplant, 2008; 23(11):3472–3478.
38.
Sancho-MartínezSM, López-NovoaJM, López-HernándezFJ. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury. Clin Kidney J, 2015; 8(5):548–559.
39.
SchwarzDS, BlowerMD. The endoplasmic reticulum: Structure, function and response to cellular signaling. Cell Mol Life Sci, 2016; 73(1):79–94.
SmithMD, HarleyME, KempAJ, et al.CCPG1 is a non-canonical autophagy cargo receptor essential for ER-phagy and pancreatic ER proteostasis. Dev Cell, 2018; 44(2):217–232.e11.
42.
SongS, TanJ, MiaoY, et al.Crosstalk of ER stress-mediated autophagy and ER-phagy: Involvement of UPR and the core autophagy machinery. J Cell Physiol, 2018; 233(5):3867–3874.
43.
SwiderekE, KalasW, WysokinskaE, et al.The interplay between epigenetic silencing, oncogenic KRas and HIF-1 regulatory pathways in control of BNIP3 expression in human colorectal cancer cells. Biochem Biophys Res Commun, 2013; 441(4):707–712.
44.
TangC, HanH, LiuZ, et al.Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury. Cell Death Dis, 2019; 10(9):677.
45.
TangC, HanH, YanM, et al.PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy, 2018; 14(5):880–897.
46.
WangNS, UnkilaMT, ReineksEZ, et al.Transient expression of wild-type or mitochondrially targeted Bcl-2 induces apoptosis, whereas transient expression of endoplasmic reticulum-targeted Bcl-2 is protective against Bax-induced cell death. J Biol Chem, 2001; 276(47):44117–44128.
47.
WuZ, ZhangW, KangYJ. Copper affects the binding of HIF-1alpha to the critical motifs of its target genes. Metallomics, 2019; 11(2):429–438.
48.
YangM, LuoS, WangX, et al.ER-Phagy: A new regulator of ER homeostasis. Front Cell Dev Biol, 2021; 9:684526.
49.
YangS, ZhaoL, HanY, et al.Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc. Redox Biol, 2017; 13:482–497.
50.
ZhangL, LiL, LeavesleyHW, et al.Cyanide-induced apoptosis of dopaminergic cells is promoted by BNIP3 and Bax modulation of endoplasmic reticulum-mitochondrial Ca2+ levels. J Pharmacol Exp Ther, 2010; 332(1):97–105.
51.
ZhangJ, NeyPA. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ, 2009; 16(7):939–946.
52.
ZhangT, XueL, LiL, et al.BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy. J Biol Chem, 2016; 291(41):21616–21629.
53.
ZhaoH, JiangN, HanY, et al.Aristolochic acid induces renal fibrosis by arresting proximal tubular cells in G2/M phase mediated by HIF-1alpha. FASEB J, 2020; 34(9):12599–12614.
54.
ZhuW, CowieA, WasfyGW, et al.Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. EMBO J, 1996; 15(16):4130–4141.
55.
ZouYF, LiaoWT, FuZJ, et al.MicroRNA-30c-5p ameliorates hypoxia-reoxygenation-induced tubular epithelial cell injury via HIF1alpha stabilization by targeting SOCS3. Oncotarget, 2017; 8(54):92801–92814.
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