Restricted accessResearch articleFirst published online 2019-3
Advanced Oxidation Protein Products Aggravate Tubulointerstitial Fibrosis Through Protein Kinase C-Dependent Mitochondrial Injury in Early Diabetic Nephropathy
Diabetic nephropathy (DN) is the most common microvascular complications and the principal cause of mortality and morbidity rates in patients with diabetes. The expression of advanced oxidation protein products (AOPPs) has been found in vacuolated renal tubules in DN and correlated with patients' decreased renal function. The accumulation of AOPPs is regarded as an initiating factor in podocyte injuries via the protein kinase C (PKC) signaling, which plays a critical role in triggering oxidative stress and mitochondrial injuries in diseases including DN. Whether AOPPs could induce mitochondrial injuries and fibrosis in renal tubules remains largely unknown. Herein, we tested the hypothesis that the accumulation of AOPPs in diabetes incurs mitochondrial dysfunction and oxidative stress, causing renal tubulointerstitial fibrosis (TIF) via PKC signaling pathway.
Results:
In vivo, intrarenal AOPPs accumulation correlated with oxidative stress, renal fibrosis, proteinuria, and declined renal function in DN patients and diabetic rats. AOPPs-induced mitochondrial injuries, apoptosis, and TIF were significantly mitigated by PKCη inhibition in diabetic rats. In vitro, high glucose (HG) stimulated AOPP expression and augmented PKC-mediated oxidative stress and fibrosis in HK-2 cells. Furthermore, we provide mechanistic evidence that inhibition of PKCη isoform alleviated mitochondrial injuries and function, attenuated apoptosis, and renal fibrosis in HG-cultured AOPPs-induced HK-2 cells.
Innovation and Conclusion:
We propose a novel mechanism that AOPPs-induced mitochondrial dysfunction and oxidative stress cause TIF in DN via activation of the PKCη isoform.
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References
1.
ArcherSL. Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med, 369: 2236–2251, 2013.
2.
AykutG, KilercikM, AriturkC, UlugolH, AksuU, KudsiogluT, AtalanN, YapiciN, KarabulutH, and ToramanF. Correction of dilutional anemia induces renal dysfunction in diabetic patients undergoing coronary artery bypass grafting: a consequence of microcirculatory alterations?. J Nephrol, 2017. DOI: 10.1007/s40620-017-0388-8
3.
BaiX, GengJ, LiX, YangF, and TianJ. VEGF-A inhibition ameliorates podocyte apoptosis via repression of activating protein 1 in diabetes. Am J Nephrol, 40: 523–534, 2014.
4.
BuhlEM, DjudjajS, BabickovaJ, KlinkhammerBM, FolestadE, Borkham-KamphorstE, WeiskirchenR, HudkinsK, AlpersCE, ErikssonU, FloegeJ, and BoorP. The role of PDGF-D in healthy and fibrotic kidneys. Kidney Int, 89: 848–861, 2016.
5.
CaoW, XuJ, ZhouZM, WangGB, HouFF, and NieJ. Advanced oxidation protein products activate intrarenal renin-angiotensin system via a CD36-mediated, redox-dependent pathway. Antioxid Redox Signal, 18: 19–35, 2013.
6.
DasF, Ghosh-ChoudhuryN, MariappanMM, KasinathBS, and ChoudhuryGG. Hydrophobic motif site-phosphorylated protein kinase CbetaII between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy. Am J Physiol Cell Physiol, 310: C583–C596, 2016.
7.
DonatoV, BonoraM, SimoneschiD, SartiniD, KudoY, SarafA, FlorensL, WashburnMP, StadtfeldM, PintonP, and PaganoM. The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells. Nat Cell Biol, 19: 341–351, 2017.
8.
DorfmanMD, KrullJE, ScarlettJM, GuyenetSJ, SajanMP, DamianV, NguyenHT, LeitgesM, MortonGJ, FareseRV, SchwartzMW, and ThalerJP. Deletion of protein kinase C lambda in POMC neurons predisposes to diet-induced obesity. Diabetes, 66: 920–934, 2017.
9.
GeJ, JiaQ, LiangC, LuoY, HuangD, SunA, WangK, ZouY, and ChenH. Advanced glycosylation end products might promote atherosclerosis through inducing the immune maturation of dendritic cells. Arterioscler Thromb Vasc Biol, 25: 2157–2163, 2005.
10.
GelisgenR, GencH, KayaliR, OnculM, BenianA, GuralpO, UludagS, CakatayU, AlbayrakM, and UzunH. Protein oxidation markers in women with and without gestational diabetes mellitus: a possible relation with paraoxonase activity. Diabetes Res Clin Pract, 94: 404–409, 2011.
11.
GewinL, ZentR, and PozziA. Progression of chronic kidney disease: too much cellular talk causes damage. Kidney Int, 91: 552–560, 2017.
12.
GnudiL. Cellular and molecular mechanisms of diabetic glomerulopathy. Nephrol Dial Transplant, 27: 2642–2649, 2012.
13.
GuoZJ, NiuHX, HouFF, ZhangL, FuN, NagaiR, LuX, ChenBH, ShanYX, TianJW, NagarajRH, XieD, and ZhangX. Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxid Redox Signal, 10: 1699–1712, 2008.
14.
HouX, TianJ, GengJ, LiX, TangX, ZhangJ, and BaiX. MicroRNA-27a promotes renal tubulointerstitial fibrosis via suppressing PPARgamma pathway in diabetic nephropathy. Oncotarget, 7: 47760–47776, 2016.
15.
JiaSN, LinC, ChenDF, LiAQ, DaiL, ZhangL, ZhaoLL, YangJS, YangF, and YangWJ. The transcription factor p8 regulates autophagy in response to palmitic acid stress via a mammalian target of rapamycin (mTOR)-independent signaling pathway. J Biol Chem, 291: 4462–4472, 2016.
16.
KabraUD, PfuhlmannK, MiglioriniA, KeipertS, LampD, KorsgrenO, GeggM, WoodsSC, PflugerPT, LickertH, AffourtitC, TschopMH, and JastrochM. Direct substrate delivery into mitochondrial fission-deficient pancreatic islets rescues insulin secretion. Diabetes, 66: 1247–1257, 2017.
17.
LeeRH and BergmeierW. Sugar makes neutrophils RAGE: linking diabetes-associated hyperglycemia to thrombocytosis and platelet reactivity. J Clin Invest, 127: 2040–2043, 2017.
18.
LiHY, HouFF, ZhangX, ChenPY, LiuSX, FengJX, LiuZQ, ShanYX, WangGB, ZhouZM, TianJW, and XieD. Advanced oxidation protein products accelerate renal fibrosis in a remnant kidney model. J Am Soc Nephrol, 18: 528–538, 2007.
19.
LiangM, LiA, LouA, ZhangX, ChenY, YangL, LiY, YangS, and HouFF. Advanced oxidation protein products promote NADPH oxidase-dependent beta-cell destruction and dysfunction through the Bcl-2/Bax apoptotic pathway. Lab Invest, 97: 792–805, 2017.
20.
LiangM, WangJ, XieC, YangY, TianJW, XueYM, and HouFF. Increased plasma advanced oxidation protein products is an early marker of endothelial dysfunction in type 2 diabetes patients without albuminuria 2. J Diabetes, 6: 417–426, 2014.
21.
LiuB, HouX, ZhouQ, TianJ, ZhuP, XuJ, HouF, and FuN. Detection of advanced oxidation protein products in patients with chronic kidney disease by a novel monoclonal antibody. Free Radic Res, 45: 662–671, 2011.
22.
McDougalAD and DeweyCFJr. Modeling oxygen requirements in ischemic cardiomyocytes. J Biol Chem, 292: 11760–11776, 2017.
23.
MillsEL, KellyB, and O'NeillLAJ. Mitochondria are the powerhouses of immunity. Nat Immunol, 18: 488–498, 2017.
24.
MirmiranpourH, MousavizadehM, NoshadS, GhavamiM, EbadiM, GhasemiesfeM, NakhjavaniM, and EsteghamatiA. Comparative effects of pioglitazone and metformin on oxidative stress markers in newly diagnosed type 2 diabetes patients: a randomized clinical trial. J Diabetes Complications, 27: 501–507, 2013.
25.
MoH, WuQ, MiaoJ, LuoC, HongX, WangY, TangL, HouFF, LiuY, and ZhouL. C-X-C chemokine receptor type 4 plays a crucial role in mediating oxidative stress-induced podocyte injury. Antioxid Redox Signal, 27: 345–362, 2017.
26.
MohammediK, Bellili-MunozN, DrissF, RousselR, SetaN, FumeronF, HadjadjS, MarreM, and VelhoG. Manganese superoxide dismutase (SOD2) polymorphisms, plasma advanced oxidation protein products (AOPP) concentration and risk of kidney complications in subjects with type 1 diabetes. PLoS One, 9: e96916, 2014.
27.
MudaliarS, AllojuS, and HenryRR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care, 39: 1115–1122, 2016.
28.
NakazawaD, KumarSV, MarschnerJ, DesaiJ, HolderiedA, RathL, KraftF, LeiY, FukasawaY, MoeckelGW, AngelottiML, LiapisH, and AndersHJ. Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J Am Soc Nephrol, 28: 1753–1768, 2017.
29.
NasriH. On the occasion of the world diabetes day 2013; diabetes education and prevention; a nephrology point of view. J Renal Inj Prev, 2: 31–32, 2013.
30.
NowakG, Takacsova-BakajsovaD, and MegyesiJ. Deletion of protein kinase C-epsilon attenuates mitochondrial dysfunction and ameliorates ischemic renal injury. Am J Physiol Renal Physiol, 312: F109–F120, 2017.
31.
OsmanC, NoriegaTR, OkreglakV, FungJC, and WalterP. Integrity of the yeast mitochondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion. Proc Natl Acad Sci U S A, 112: E947–E956, 2015.
32.
ParatiG, BiloG, and OchoaJE. Benefits of tight blood pressure control in diabetic patients with hypertension: importance of early and sustained implementation of effective treatment strategies. Diabetes Care 34 Suppl, 2: S297–S303, 2011.
33.
PayneGA, BorbouseL, KumarS, NeebZ, AllooshM, SturekM, and TuneJD. Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler Thromb Vasc Biol, 30: 1711–1717, 2010.
34.
PommierY, SunY, HuangSN, and NitissJL. Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat Rev Mol Cell Biol, 17: 703–721, 2016.
35.
QiW, KeenanHA, LiQ, IshikadoA, KanntA, SadowskiT, YorekMA, WuIH, LockhartS, CoppeyLJ, PfenningerA, LiewCW, QiangG, BurkartAM, HastingsS, PoberD, CahillC, NiewczasMA, IsraelsenWJ, TinsleyL, StillmanIE, AmentaPS, FeenerEP, Vander HeidenMG, StantonRC, and KingGL. Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med, 23: 753–762, 2017.
36.
SabounyR, FraunbergerE, GeoffrionM, NgA, BairdS, ScreatonR, MilneR, McBrideHM, and ShuttT. The Keap1-Nrf2 stress response pathway promotes mitochondrial hyperfusion through degradation of the mitochondrial fission protein Drp1. Antioxid Redox Signal, 27: 1447–1459, 2017.
37.
This reference has been deleted.
38.
This reference has been deleted.
39.
SlyneJ, SlatteryC, McMorrowT, and RyanMP. New developments concerning the proximal tubule in diabetic nephropathy: in vitro models and mechanisms. Nephrol Dial Transplant 30 Suppl, 4: iv60–iv67, 2015.
40.
ThaiV, DephoureN, WeissA, FergusonJ, LeitaoR, GygiSP, and KelloggDR. Protein kinase C controls binding of Igo/ENSA proteins to protein phosphatase 2A in budding yeast. J Biol Chem, 292: 4925–4941, 2017.
41.
Thallas-BonkeV, ThorpeSR, CoughlanMT, FukamiK, YapFY, SourrisKC, PenfoldSA, BachLA, CooperME, and ForbesJM. Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway. Diabetes, 57: 460–469, 2008.
42.
WanJ, HouX, ZhouZ, GengJ, TianJ, BaiX, and NieJ. WT1 ameliorates podocyte injury via repression of EZH2/beta-catenin pathway in diabetic nephropathy. Free Radic Biol Med, 108: 280–299, 2017.
43.
WangF, XuC, ReeceEA, LiX, WuY, HarmanC, YuJ, DongD, WangC, YangP, ZhongJ, and YangP. Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy. Nat Commun, 8: 15182, 2017.
44.
WangJ, LiangM, XuJ, CaoW, WangGB, ZhouZM, TianJW, JiaN, ZhangZ, NieJ, LiuY, and HouFF. Renal expression of advanced oxidative protein products predicts progression of renal fibrosis in patients with IgA nephropathy. Lab Invest, 94: 966–977, 2014.
45.
WangL, BalzerMS, RongS, MenneJ, von VietinghoffS, DongL, GuelerF, JangMS, XuG, TimrottK, TkachukS, HissM, HallerH, and ShushakovaN. Protein kinase C alpha inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate. Kidney Int, 89: 1253–1267, 2016.
46.
WangXX, WangD, LuoY, MyakalaK, DobrinskikhE, RosenbergAZ, LeviJ, KoppJB, FieldA, HillA, LuciaS, QiuL, JiangT, PengY, OrlickyD, GarciaG, Herman-EdelsteinM, D'AgatiV, HenriksenK, AdoriniL, PruzanskiM, XieC, KrauszKW, GonzalezFJ, RanjitS, DvornikovA, GrattonE, and LeviM. FXR/TGR5 dual agonist prevents progression of nephropathy in diabetes and obesity. J Am Soc Nephrol, 29: 118–137, 2018.
47.
WangY, DingM, ChaudhariS, DingY, YuanJ, StankowskaD, HeS, KrishnamoorthyR, CunninghamJT, and MaR. Nuclear factor kappaB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells. J Biol Chem, 288: 12852–12865, 2013.
48.
WeiXF, ZhouQG, HouFF, LiuBY, and LiangM. Advanced oxidation protein products induce mesangial cell perturbation through PKC-dependent activation of NADPH oxidase. Am J Physiol Renal Physiol, 296: F427–F437, 2009.
49.
WuY, ChenY, ChenD, ZengC, LiL, and LiuZ. Presence of foam cells in kidney interstitium is associated with progression of renal injury in patients with glomerular diseases. Nephron Clin Pract, 113: c155–c161, 2009.
50.
XuX, SunS, XieF, MaJ, TangJ, HeS, and BaiL. Advanced oxidation protein products induce epithelial-mesenchymal transition of intestinal epithelial cells via a PKC delta-mediated, redox-dependent signaling pathway. Antioxid Redox Signal, 27: 37–56, 2017.
51.
This reference has been deleted.
52.
ZhangX, ZhangZ, ZhaoY, JiangN, QiuJ, YangY, LiJ, LiangX, WangX, TseG, LiG, and LiuT. Alogliptin, a dipeptidyl peptidase-4 inhibitor, alleviates atrial remodeling and improves mitochondrial function and biogenesis in diabetic rabbits. J Am Heart Assoc 6:, pii: e005945, 2017.
53.
ZhouLL, HouFF, WangGB, YangF, XieD, WangYP, and TianJW. Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms. Kidney Int, 76: 1148–1160, 2009.
54.
ZhouZ, WanJ, HouX, GengJ, LiX, and BaiX. MicroRNA-27a promotes podocyte injury via PPARgamma-mediated beta-catenin activation in diabetic nephropathy. Cell Death Dis, 8: e2658, 2017.
55.
ZhuK, KakehiT, MatsumotoM, IwataK, IbiM, OhshimaY, ZhangJ, LiuJ, WenX, TayeA, FanC, KatsuyamaM, SharmaK, and Yabe-NishimuraC. NADPH oxidase NOX1 is involved in activation of protein kinase C and premature senescence in early stage diabetic kidney. Free Radic Biol Med, 83: 21–30, 2015.
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