Targeting Energy Pathways in Kidney Disease: Lub luag hauj lwm ntawm Sirtuins, AMPK, Thiab PGC1 Part 1
Apr 18, 2023
Abstract
Lub raum muaj qhov xav tau tshwj xeeb hauv metabolic los txhawb nqa kev thauj mus los ntawm cov kuab tshuaj uas tseem ceeb rau lub raum pom thiab tshem tawm. Mitochondrial kev noj qab haus huv yog qhov tseem ceeb los ua kom tau raws li qhov xav tau thiab tswj lub raum kom zoo. Ntau xyoo ntawm kev tshawb fawb tau txuas cov kev noj qab haus huv mitochondrial tsis zoo rau cov kab mob raum. Cov kws tswj hwm tseem ceeb ntawm mitochondrial noj qab haus huv - 5-AMP-activated protein kinase (AMPK), sirtuins, thiab peroxisome proliferator-activated receptor coactivator-1alpha (PGC1) - tau pom tias muaj lub luag haujlwm tseem ceeb hauv lub raum ua haujlwm tiv thaiv. kab mob. Qhov kev tshuaj xyuas no yuav qhia txog cov kev tshawb fawb tshiab tshaj plaws rau cov dej num ntawm cov tswj hwm thiab tshuaj xyuas lub luag haujlwm thiab kev kho lub peev xwm ntawm kev tsom mus rau cov tswj hwm hauv kev mob raum mob, kab mob glomerular raum, thiab lub raum fibrosis.
Cistancheyog ib hom tshuaj suav tshuaj uas ntseeg tau tias muaj ntau yam txiaj ntsig kev noj qab haus huv suav nrogtxhim kho lub raum ua haujlwm. Tshuaj ntsuab xav tias muaj ibtonifying nyhuv ntawm lub raumthiab feem ntau yog siv rau hauv kev kho mob ntawmlub raum tsis muaj peev xwmthiab lwm yam mob xws liimpotence, infertility, thiab tso zis ntau zaus. Txawm hais tias muaj qee cov pov thawj los qhia tias cistanche tuaj yeem pab tautxhim kho lub raum ua haujlwm, xav tau kev tshawb fawb ntxiv kom nkag siab txog nws cov teebmeem ntawm cov kab mob raum. Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias cistanche yuav tsum tsis txhob siv los hloov kev kho mob thiab cov neeg muaj kab mob raum yuav tsum sab laj nrog lawv tus kws kho mob ua ntej siv tshuaj ntsuab.
Nyem rau ntawm Cistanche Tubulosa Rau Raum Kab Mob
Yog xav paub ntxiv:
david.deng@wecistanche.com WhatApp:86 13632399501
Ntsiab lus
mitochondria; mob raum mob; mob ntshav qab zib nephropathy; fibrosis; proteinuria
Taw qhia
Txhawm rau tswj hwm qib sodium hauv ib txwm, tib neeg lub raum yuav tsum lim thiab rov nqus tau ze li 20, 000 milliequivalents ntawm sodium txhua hnub, uas yog tshaj li ib phaus ntawm sodium nquag reabsorbed tawm tsam ib puas-fold gradient. Tsis xav tsis thoob, cov hlwb tshwj xeeb uas ua cov haujlwm ntawd xav tau lub zog loj heev. Vim tias qhov kev cia siab ntawm lub zog no, ib lub cev loj ntawm cov ntaub ntawv tau nug seb lub raum puas muaj feem cuam tshuam rau cov metabolic insults thiab yog tias cov susceptibilities muaj peev xwm kho tau. Peroxisome proliferator-activated receptor (PPAR) coactivator-1alpha (PGC1), ua tus tswj hwm ntawm mitochondrial biogenesis, thiab cov enzymes uas tswj PGC1 muaj peev xwm loj heev hauv qhov hais txog.
PGC1 yog ib tug tswv cuab ntawm PGC1 tsev neeg ntawm transcriptional coactivators, nrog rau PGC1 thiab PGC1 -txog coactivators (PRC), uas ua lub luag hauj lwm tswj nyob rau hauv metabolic homeostasis los ntawm "boosting" cov kev ua ntawm nuclear receptors. PGC1 tshwj xeeb ua tus tswj hwm ntawm mitochondrial biogenesis. PGC1 tau piav qhia thawj zaug hauv xyoo 1998 thaum ib pab pawg txaus siab rau kev rog rog thiab kev tswj hwm ntawm cov rog rog xim av uncoupling proteins tau txheeb xyuas cov protein no ua lub zog transcriptional coactivator rau PPAR .1 Lawv tau pom tias PGC1 tau nthuav tawm heev tom qab raug mob khaub thuas nrog ib txhij nce hauv kev qhia ntawm uncoupling. cov proteins, uas cuam tshuam cov mitochondrial proton gradient los ua kom sov. Tsis ntev tom qab ntawd, lub luag haujlwm dav dav ntawm PGC1 tau piav qhia. Ntxiv nrog rau "nkim" metabolic kub zog ntawm kev sib txuas, PGC1 tau pom los tswj ntau qhov kev pabcuam los tswj tag nrho lub zog sib npaug los ntawm kev nthuav tawm oxidative phosphorylation noob thiab nce mitochondrial biogenesis los ntawm upregulated mitochondrial DNA proliferation thiab nce kev qhia ntawm cov ntsiab lus tseem ceeb mitochondrial transcription, nuclear respiratory factor (NRF1/2) thiab mitochondrial transcription factor A (TFAM).2 Tag nrho cov kev ua ua ke, PGC1 tau tshwm sim los ua lub zog inducer ntawm kev ua pa muaj peev xwm txawm tias lub zog poob los ntawm kev tsis sib txuas.
PGC1 Txoj Cai thiab Cov Txheej Txheem
Ntxiv rau qhov raug mob khaub thuas, ntau lwm yam stimuli tau pom tias yuav ua rau PGC1 qhia nrog rau kev tawm dag zog ntawm AMPK, 3 calorie txwv, oxidative kev nyuaj siab ntawm SIRT1,4, thiab hypoxia ntawm AMPK (Daim duab 1.5). kev ua haujlwm ntawm mitochondrial. Qhov tseem ceeb tshaj plaws, nws txhawb nqa mitochondrial biogenesis los ntawm kev txhais lus ntau ntxiv ntawm TFAM thiab NRF1/2.6, 7 Tab sis PGC1 kuj tseem txhawb nqa kev tiv thaiv oxidative kev nyuaj siab los ntawm kev ua kom SIRT 3,4, 8 txhim kho kev noj qab haus huv ntawm lub pas dej mitochondrial los ntawm kev ua kom cov tshuaj estrogen-txog receptor- ( ERR ) thiab cov khoom siv hloov pauv EB (TFEB) txhawm rau txhim kho mitochondrial dynamics, 9 txhawb nqa biosynthesis ntawm nicotinamide adenine dinucleotide (NAD ntxiv), 10, 11 thiab txhawb nqa oxidation ntawm fatty acids los ntawm PPARs thiab retinoid X receptors (RXRs).12, PGC. tuaj yeem raug downregulated los ntawm ntau yam ib txwm muaj feem cuam tshuam rau hauv pro-inflammatory thiab pro-fibrotic cascades xws li qog necrosis factor- (TNF), transforming growth factor- (TGF), thiab tus xov tooj zoo li receptor 4 (TLR4).14-16 PGC1 yog. upregulated los ntawm ntau yam metabolically tseem ceeb transcription yam xws li hepatocyte nuclear factor 1 homeobox- (HNF1 ), TFEB, thiab pyruvate kinase M2 (PKM2).17–19 Ib zaug qhia, PGC1 protein tuaj yeem dhau mus tom qab kev hloov pauv hloov pauv uas hloov nws txoj haujlwm. Qhov kev nkag siab zoo tshaj plaws, thiab tej zaum tseem ceeb tshaj plaws, PGC1 kev hloov pauv tom qab kev txhais lus yog phosphorylation los ntawm 5-AMP-activated protein kinase (AMPK) thiab deacetylation los ntawm Sirtuin1 (SIRT1). Kev sib tham ntxaws ntxaws ntawm PGC1 txoj cai yog nyob sab nraud ntawm qhov kev tshuaj xyuas no vim tias tsab xov xwm no yuav tsom mus rau PGC1 cov teebmeem hauv lub raum. Peb yuav tham luv luv AMPK thiab sirtuins, feem ntau thaum lawv ua haujlwm los ntawm PGC1, tab sis kev sib tham ntau ntxiv ntawm PGC1 txoj cai tau tshaj tawm yav dhau los.20
AMPK
AMPK ua raws li kev saib xyuas thiab tiv thaiv lub zog ntawm tes xav tau los ntawm ob txoj haujlwm tseem ceeb: inhibition ntawm kev siv hluav taws xob thiab kev txhawb zog ntawm kev tsim hluav taws xob. Txoj hauv kev Anabolic uas siv lub zog los tsim thiab khaws cov molecules loj dua yog qhov cuam tshuam dav dav los ntawm AMPK. Piv txwv li, HMG-CoA reductase catalyzes tus nqi-txheej theem ntawm cov roj cholesterol synthesis thiab yog inhibited raws li phosphorylation los ntawm AMPK.21 Ib yam li ntawd, AMPK phosphorylates thiab inhibits acetyl-CoA carboxylase ACC1 thiab ACC2, uas pib thawj kauj ruam hauv lipid synthesis. inhibits glycogen cia los ntawm inactivating glycogen synthases GYS1 thiab GYS223 thiab gluconeogenesis los ntawm inactivating CREB Regulated Transcription Coactivator 2 (CRTC2), ib tug muaj zog activator ntawm ntau gluconeogenic noob. ATP khw muag khoom. Lub hom phiaj mammalian ntawm rapamycin (mTOR) yog lub hauv paus kinase uas txhawb kev loj hlob ntawm tes. AMPK inhibits mTOR los ntawm deactivating Raptor, ib qho protein uas complexes nrog mTOR kom qhib cov protein txhais lus thiab cellular loj hlob.25 AMPK ntxiv phosphorylates thiab activates Eukaryotic Elongation Factor 2 Kinase (eEF2K), uas inhibits protein elongation.26
Txhawm rau ua kom muaj zog, AMPK txhawb nqa cov catabolism ntawm macromolecules, nce kev siv cov piam thaj, thiab txhawb cov khw muag khoom lipid. Los ntawm deactivating Raptor, AMPK tshem tawm lub ntuj nres ntawm autophagy, cov txheej txheem uas cov khoom ntawm tes tau tawg thiab rov ua dua. Nrog cov nquag Raptor, mTOR complexes inhibit autophagy los ntawm phosphorylation Unc-51 Zoo li Autophagy Activating Kinase 1 (ULK1).25 AMPK kuj ncaj qha activates ULK1 los txhawb autophagy.27 Txhawm rau kom cov cellular qabzib nkag thiab siv, AMPK txhawb nqa cov membrane localization ntawm qabzib. transporters GLUT1 thiab GLUT428 thiab nkoos qabzib flux los ntawm glycolysis los ntawm activating tus nqi-limiting enzyme nyob rau hauv glycolysis, phosphofructokinase-1.29 AMPK kuj activates lipases kom tso tawm fatty acids los ntawm triglyceride khw muag khoom30 thiab induces fatty acid ntshuam los ntawm maximateria inactivon. CoA ntau lawm, li no alleviating inhibition ntawm Carnitine palmitoyltransferase I (CPT1), tus nqi-limiting enzyme rau mitochondrial fatty acid oxidation (Daim duab 2.31).
Thaum kawg, AMPK ua lub luag haujlwm dav hauv kev tswj hwm mitochondrial homeostasis thiab ua kom zoo dua oxidative phosphorylation, lub xov tooj ntawm cov txheej txheem ua kom muaj zog tshaj plaws. Qhov tseem ceeb tshaj plaws, AMPK txhawb nqa mitochondrial biogenesis los ntawm kev ua kom PGC1. AMPK phosphorylates tsawg kawg yog ob qhov tshwj xeeb PGC1 qhov chaw32 thiab tseem cuam tshuam PGC1 los ntawm kev ua kom SIRT1 thiab TFEB.18, 33 Raws li tau hais los saum no, AMPK tso tawm CPT1 inhibition. Qhov no txhawb nqa kev thauj cov fatty acids mus rau hauv mitochondria qhov chaw uas lawv tau txais kev sib txuas -oxidation los ua cov roj tseem ceeb rau lub voj voog Krebs thiab cov saw hlau thauj hluav taws xob (ETC). thiab fusion kom tswj tau qhov loj me, zoo, thiab kev noj qab haus huv tag nrho. Nyob rau hauv lub xub ntiag ntawm mitochondrial kev nyuaj siab, cov txheej txheem dynamic ib txwm tsis tuaj yeem ua kom nrawm, thiab mitochondria undergo fragmentation.34 AMPK qhib cov thawj receptor rau dynamin-zoo li protein (DRP1), ib qho tseem ceeb ntawm mitochondrial fission.35 Ib yam li ntawd, lub AMPK-activated ULK1 txoj kev autophagy induces mitochondrial autophagy - hu ua mitophagy - kom tshem tawm cov kev puas tsuaj mitochondria.36 Hauv cov ntsiab lus, AMPK ua tus saib xyuas qhov tseeb ntawm kev siv hluav taws xob los ntawm kev txo cov anabolism, txhim kho cov roj catabolism los tsim lub zog, thiab multidimensionally optimizing mitochondrial.
Hauv kab mob raum, AMPK tau pom tias tiv thaiv fibrosis, mob ntshav qab zib raum (DKD), thiab mob raum mob (AKI). AMPK qhia tau txo qis lub raum fibrosis los ntawm kev noj zaub mov muaj rog, kev laus, folic acid nephropathy, thiab ureteral obstruction hauv nas. 37–40 Kev ua kom AMPK kuj txo qis ntshav qab zib nephropathy hauv cov nas thiab txo qis hyperglycemia-txog kev qhia ntawm cov noob fibrosis hauv podocytes.41, 42 AMPK ua kom txo qis kev raug mob ntawm tubular hauv nas thiab nas kis rau cisplatin.43-45 Cov kab mob ua ntej thiab cov kab mob nas. nrog AMPK activators txo qhov hnyav ntawm lub raum mob ischemic.46 Los ntawm nws cov kev ua dav dav, AMPK kev ua feem ntau cuam tshuam nrog kev txhim kho cov txiaj ntsig tom qab muaj ntau yam kev sim rau lub raum insults. Thaum qhov kev tshuaj xyuas no tsom mus rau PGC1 ua kom muaj zog, lwm yam AMPK-tsav los kuj tseem ceeb rau kev kawm ntxiv raws li txoj hauv kev los hloov kho raum kab mob.
Sirtuins
Sirtuins yog ib chav kawm ntawm NAD ntxiv rau -siv deacetylases uas nthuav tawm ntau cov haujlwm ntawm tes. Ob qhov kev kawm ntau tshaj plaws, thiab ob qho tseem ceeb tshaj plaws rau qhov kev tshuaj xyuas no, yog SIRT1 thiab SIRT3. SIRT1 nyob hauv lub nucleus uas nws tswj cov haujlwm ntawm cov ntsiab lus tseem ceeb. Los ntawm inhibiting NFκB ntawm deacetylation, SIRT1 txo qis TNF signaling kom muaj kev tiv thaiv kab mob.47 SIRT1 kuj txo cov cellular senescence, cell tuag, thiab susceptibility to oxidative stress by deacetylating p5348 thiab forehead box type O (FoxO) transcription factors.49 SIRT1 txhawb nqa. erythropoietin qhia nyob rau hauv cov lus teb rau hypoxia los ntawm regulating hypoxia-inducible factor-2 .50 Nws kuj txhawb mitochondrial biogenesis los ntawm deacetylating thiab activating PGC1 .51 (Daim duab 2)SIRT3 nyob hauv mitochondrial matrix qhov twg nws deacetylates ib qho nyuaj ntawm ETC, suav nrog adenosine triphosphate (ATP) synthase, txhawm rau txhawb ATP ntau lawm.52, 53 SIRT3 kuj txo oxidative kev nyuaj siab los ntawm kev khi ncaj qha thiab hloov kev ua haujlwm ntawm ntau lub mitochondr. ntau lawm los yog tshem tawm cov reactive oxygen hom (ROS) xws li -Ketoglutarate dehydrogenase (KGDH), 54 electron flavoprotein dehydrogenase (ETFDH), 55 thiab superoxide dismutase 2 (SOD2).8 Thaum kawg, SIRT3 nce mitochondrial roj mov los ntawm deacetylation ntawm long-chainacyl. -coenzyme A dehydrogenase (LCAD), uas txhim kho fatty acid -oxidation.56 Nyob rau hauv tej zaum ib tug pab tau oversimplification, SIRT1 broadly counteracts kev nyuaj siab los ntawm kev tiv thaiv inflammatory dab uas kuj nce PGC1.qhia, thaum SIRT3 ua haujlwm tshwj xeeb los txhawb kev ua haujlwm mitochondrial thiab ua pa ntawm tes.
Cov kev tshawb fawb dav dav tau piav qhia txog kev tiv thaiv lub luag haujlwm rau sirtuins hauv lub raum kab mob.57 Kev nthuav qhia ntawm SIRT1 thiab SIRT3 tau txo qis hauv lub raum laus.58-60 Kev poob ntawm SIRT1 nrawm glomerulosclerosis thiab albuminuria hauv cov nas laus, 61 thaum kev txhim kho tau cuam tshuam nrog kev ua neej ntev.58– 62 SIRT1 attenuated raum fibrosis nyob rau hauv nas nrog ureteral obstruction63 thiab 5/6 nephrectomy64, 65 thaum SIRT3 mitigated hypertension-associated fibro sis.66 Hauv AKI, sirtuins yog downregulated los ntawm tsis paub mechanisms. SIRT3 knockout ua rau muaj kev raug mob hnyav dua hauv tus nas sepsis qauv.67 Kev sim ua haujlwm ntawm SIRT1 tiv thaiv kev raug mob ischemia-reperfusion (IRI); 68 SIRT3 overexpression tiv thaiv sepsis-associated AKI; 69 thiab ob qho tib si overexpression ntawm SIRT1 lossis pharmacologic activation ntawm SIRT3 tiv thaiv cisplatin-induced raug mob.70, 71 Hauv tib neeg glomeruli, ntshav qab zib txo SIRT1, uas ua rau albuminuria thiab kab mob kev loj hlob hauv nas.72
Sab nraud ntawm SIRT1 thiab SIRT3, lwm cov sirtuins ua lub luag haujlwm hauv lub raum kab mob, txawm tias tej zaum tsis nyob rau hauv kev sib tham ncaj qha nrog PGC1. SIRT6 tau hloov kho hauv tus qauv nas fibrosis, thiab inhibition lossis genetic knockout ua rau muaj mob fibrosis73 thiab mob raum mob hnyav dua.74 Hauv cov qauv cellular, SIRT6 cuam tshuam nrog -catenin rau deacetylate histones thiab tiv thaiv fibrogenic noob qhia.73 SIRT7 thiab SIRT5 yuav tsis yog renoprotective zoo li lwm cov sirtuins. Piv txwv li, knockout ntawm SIRT7, lwm histone deacetylase, ua rau txo qis kev qhia ntawm TNF thiab tiv thaiv cisplatin-induced AKI.75 Knockout ntawm SIRT5, ib tug lysine deacetylase, mitigated raum raug mob tom qab IRI los yog cisplatin kev kho mob los ntawm impairing qhov sib npaug ntawm mitochisomondrial thiab peripheral. -oxidation.76 Hauv cov qauv ntawm tes, SIRT5 tau tshwm sim ntau dua kev tiv thaiv raws li overexpression alleviated cisplatin raug mob.77 Raws li nrog AMPK, lub luag hauj lwm dav ntawm sirtuins hauv kev tshawb fawb rau lub raum kev kho mob yog ib qho chaw ua haujlwm ntawm kev kawm.
PGC1 thiab kab mob raum
Nyob rau hauv lub raum, PGC1 yog heev nthuav nyob rau hauv lub raum cortex thiab lub corticomedullary hlws ris, thaj chaw uas cellular respiration yog siab tshaj.78 PGC1 tau lug kawm raws li ib feem ntawm ib tug dav siv zog kom nkag siab txog lub luag hauj lwm ntawm mitochondrial kev noj qab haus huv nyob rau hauv lub raum kis kab mob. mitochondria txawv txav tau cuam tshuam nrog tib neeg lub raum raug mob txij li thaum ntxov electron microscopy kev tshawb fawb los ntawm 1970s.79 Kev tshawb fawb tsis ntev los no tau pom tias cov hlwb ntawm lub raum tubule enduring AKI tsim mitochondrial dysfunction nrog tsawg dua oxygen noj, 80 txuam ntawm fatty acids, 81. Kev puas tsuaj biosyntheses ntawm NAD ntxiv ,82 txo qis mitochondrial biogenesis, thiab hloov pauv ntawm mitochondrial dynamics deb ntawm lub xeev fused. Txhua qhov kev hloov pauv no ua rau txo qis lub pas dej zoo nkauj ntawm mitochondria uas tsim nyog rau lub raum kev noj qab haus huv thiab kev ua haujlwm.83 Lub cev loj hlob ntawm cov ntaub ntawv tau pom tias PGC1 tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev txo qis tsis yog AKI nkaus xwb tab sis kuj muaj kab mob glomerular raum thiab lub raum fibrosis.
PGC1 thiab mob raum mob hnyav
Nyob rau hauv lub raum, lub raum tubular hlwb muaj ntau tshaj nyob rau hauv mitochondria, feem ntau oxidative, thiab feem ntau cuam tshuam los ntawm AKI. Txawm li cas los xij, AKI-koom nrog mitochondrial dysfunction tsis yog ib qho kev sib koom ua ke ntawm kev txo qis hauv lub raum cov ntshav khiav thiab xa oxygen; Qhov tseeb ntawm cov ntaub so ntswg cov pa oxygen tsis zoo li hloov pauv txawm tias nyob rau hauv qhov chaw ntawm cov pa oxygen tsawg.78 Lub pas dej mitochondrial ua "mob" hauv kev teb rau ischemic, inflammatory, lossis toxic stress. Kev txheeb xyuas cov txheej txheem uas mitochondria cuam tshuam los ntawm AKI tuaj yeem ua rau cov tswv yim ua kom zoo rau kev noj qab haus huv ntawm lub raum mitochondrial pas dej ua ke los tiv thaiv thiab tawm tsam AKI.
Yuav luag txhua lub ntsej muag ntawm mitochondrial kev ua haujlwm tsis zoo hauv AKI tsis hais txog etiology (Daim duab 3). Mitochondrial o yog ib qho tseem ceeb ntawm tib neeg lub raum ischemia, txawm tias thaum AKI tsis tshwm sim; 84 nws yog ib qho kev tshawb pom nyob rau hauv cov qauv kev sim ntawm AKI thiab suav tias yog cov pov thawj ntawm mitochondrial depolarization thiab dysfunction.85, 86 Toxic, inflammatory , thiab ischemic cov ntaub ntawv ntawm AKI ua rau cortical tsub zuj zuj ntawm triglycerides, uas yuav ua tau peroxidated thiab ntxiv exacerbate raum raug mob.87, 88 Mitochondrial dynamics kuj hloov los ntawm AKI, ua rau txo fusion, nce fragmentation, nce tso tawm ntawm cytochrome C thiab ROS, thiab nce apoptosis.45, 71, 89 Cov kev cuam tshuam uas hloov mitochondrial dynamics kom deb ntawm fragmentation, los ntawm SIRT1 activation los yog tshwj xeeb los ntawm kev tawm tsam ntawm fission mediator DRP1, tau pom tias txo qhov hnyav ntawm AKI.71, 90 Cellular respiration kuj yog. Qhov tseem ceeb tsis zoo hauv AKI nrog kev txo qis oxygen noj, txo cov kev qhia ntawm ETC cov khoom xws li ATP synthase, depolarization ntawm mitochondrial membrane, txo qis mitochondrial NAD ntxiv rau qib, thiab txo qis ATP ntau lawm.10, 78, 91, 92
Cov ntaub ntawv pov thawj los ntawm IRI thiab sepsis qauv qhia tau hais tias mitochondrial kev noj qab haus huv tsis zoo coj lub zog tsim kom hloov los ntawm oxidative phosphorylation mus rau glycolysis nyob rau hauv tubular epithelial hlwb ua rau raug mob, txawm hais tias lub triggering mechanisms ntawm qhov kev hloov no tsis tau elucidated.93, 94 Cov hlwb uas hloov rov qab mus rau. oxidative respiration thaum kawg rov zoo, thaum cov uas tsis tuaj yeem rov qab oxidative phosphorylation atrophied thiab pab txhawb kev txhim kho fibrosis.94 inhibiting glycolytic hloov nrog 2-deoxyglucose (2DG) hauv hlwb ua rau txhim kho mitochondrial muaj nuj nqi, 93 thaum inhibiting theem kawg ntawm glycolysis ntawm lub raum tubular tshwj xeeb knockout ntawm PKM2 coj mus rau tiv thaiv IRI.95 Lwm yam kev cuam tshuam uas tiv thaiv lub mitochondrial membrane muaj peev xwm, khaws cia ATP synthase thiab ATP ntau lawm, los yog ntxiv NAD ntxiv rau qib tau pom tias yuav txo tau lub raum raug mob. 10, 96, 97 ib
PGC1, nrog rau nws lub hom phiaj nqes hav, tau tshaj tawm dav dav tias yuav raug txo qis hauv AKI.10, 78, 98–100 Hauv tus qauv septic nas, ob qho tib si kev qhia ntawm PGC1 nws tus kheej thiab kev qhia ntawm downstream ETC Cheebtsam thiab -oxidation enzymes tau suppressed. nyob rau hauv ncaj qha proportional rau lub raum raug mob hnyav. Tsis tas li ntawd, cov ntaub ntawv teev tseg ntawm PGC1 thiab nws lub hom phiaj tau rov qab los nrog kev daws teeb meem raug mob.78 PGC1 cov nas nas khawm tau raug mob ntau dua rau AKI los ntawm sepsis, folic acid, thiab cisplatin, 11, 78, 99 thaum cov nas nrog rau lub raum tubule tshwj xeeb PGC1 overexpression tau zoo dua tiv thaiv IRI. thiab cisplatin-induced AKI.10, 11 Modulating upstream regulators ntawm PGC1 tau qhia cov teebmeem zoo sib xws: AICAR thiab resveratrol-feem ntau, me me molecule activators ntawm AMPK thiab sirtuins-txo qhov mob ntawm cisplatin AKI thiab raum ischemic raug mob14, PGC1est tuaj yeem ua rau muaj kev puas tsuaj hauv AKI thaum nws cov neeg nruab nrab hauv nruab nrab raug cuam tshuam, uas muaj feem cuam tshuam los ntawm oxidative dawb radicals thiab lwm yam tshuaj lom neeg ntawm cov neeg raug mob mitochondria. Piv txwv li, inhibiting lysosomes nrog chloroquine thiab yog li inhibiting PGC1 cov txiaj ntsig zoo ntawm mitophagy induction tsis tsuas yog tshem tawm cov kev tiv thaiv ntawm PGC1 tab sis ua rau PGC1 overexpression toxicity nrog phem cisplatin-induced nephrotoxicity thiab nce oxidative stress.11
Tseem muaj ntau yam uas yuav tsum tau kawm txog cov txheej txheem uas txuas AKI thiab PGC1 kev tawm tsam. Nws tau nkag siab zoo tias sirtuins tuaj yeem raug txo qis hauv AKI; 67 thiab tseem hais tias biosynthesis ntawm NAD ntxiv, ib qho tsim nyog cofactor rau sirtuin muaj nuj nqi, txo qis hauv AKI.10, 82 Kuj tseem muaj pov thawj tias cov kab mob inflammatory txuas nrog TLR4, IL{{ 5}}, NKκ , thiab ERK1/2—tag nrho cov uas inhibit PGC1 — yog upregulated hauv AKI; thaiv cov kab mob inflammatory no xws li caj ces lossis nrog lub hom phiaj pharmacologic tuaj yeem tiv thaiv PGC1 qib thiab txo lub raum raug mob hauv cov qauv tsiaj.16, 98, 104 Ntxiv rau qhov kev qhia ntxiv txog kev sib cuam tshuam ntawm PGC1 regulators thiab effectors yuav yog qhov tseem ceeb rau kev tsim kho AKI hom phiaj.
PGC1 thiab Glomerular Disease
Thaum nyob rau hauv situ hybridization imaging tsis qhia muaj zog localization ntawm PGC1 rau lub glomerulus, 78 ntau yam kev tshawb fawb tau delineated lub luag hauj lwm tseem ceeb rau no transcriptional coactivator nyob rau hauv kev tswj glomerular noj qab haus huv. Lub luag haujlwm ntawd tau kawm tau zoo tshaj plaws los ntawm lub lens ntawm DKD.105 (Daim duab 4) Kev kuaj mob metabolic ntawm tib neeg lub raum tau pom lub vaj huam sib luag ntawm ntau cov metabolites uas cuam tshuam txog kev ua haujlwm ntawm mitochondrial hauv lub raum mob ntshav qab zib. Ib yam li ntawd, lub raum cortex ntawm cov neeg mob DKD tau pom qhov txo qis ntawm PGC1 .106 Qhov no tsawg kawg yog ib feem ntawm kev txo qis ntawm cov PGC1 tseem ceeb regulators nrog rau sirtuins72, 107, thiab FoxO1.108 Qhov tseeb, muaj pov thawj tias cov podocyte muaj peev xwm ua tau. tswj mitochondrial biogenesis yog impaired hauv ntshav qab zib. RNA sequencing ntawm glomeruli qhia tau hais tias ntev noncoding RNA (lncRNA) hu ua taurine-upregulated gene 1 (Tug1) txo qis hauv cov ntshav qab zib glomeruli. Tug1 tau tshwm sim los khi rau sab sauv ntawm PPARGC1A locus los txhim kho PGC1 kev qhia. Tsis tas li ntawd, Tug1 cuam tshuam nrog PGC1 txhawm rau nce PGC1 kev qhia ntxiv. Podocyte-specific overexpression of Tug1 nyob rau hauv cov nas mob ntshav qab zib ua rau nce PGC1 kev qhia, txhim kho hyperglycemia-sociated histology, thiab txo qis albuminuria.109 Ib qho kev tshawb fawb ntxiv tau pom tias cov ntshav qab zib aberrations hauv txoj kev glycolytic cuam tshuam PGC1 hauv kev kho mob tseem ceeb. Kev tsom xam cov tshuaj tiv thaiv kab mob glomeruli los ntawm cov neeg mob ntshav qab zib mellitus nrog thiab tsis muaj kab mob hauv lub raum qhia tau tias cov neeg mob ntshav qab zib tsis muaj kab mob hauv lub raum tau nce kev ua haujlwm ntawm cov txheej txheem metabolic. Tshwj xeeb, PKM2, qhov kawg enzyme ntawm txoj kev glycolytic, tau raug kho. Hyperglycemia tau pom tias txo qis PKM2 thaum podocyte-tshwj xeeb PKM2 tshem tawm nas tau tsim mob nephropathy. Intriguingly, ib qho me me-molecule PKM2 activator ua rau nce PGC1 qhia thiab thim rov qab ntawm hyperglycemia-induced metabolic abnormalities thiab mitochondrial dysfunction.19
Kev txo qis ntawm PGC1 hauv hyperglycemia ua rau muaj kev cuam tshuam ntawm mitochondrial dynamics nrog nce mitochondrial fragmentation thiab impaired cellular respiration.110 Nce PGC1 los ntawm overexpression los yog pharmacologic stimulation ntawm SIRT1 txo albuminuria nyob rau hauv cov nas mob ntshav qab zib thiab kev tiv thaiv cov ntshav qab zib reactive podocytes. mitochondrial membrane muaj peev xwm, thiab impaired autophagy. 72, 107, 111, 112 Kev nthuav qhia ntau dhau ntawm PGC1 lub hom phiaj siv PPAR agonist, rosiglitazone, tiv thaiv kab mob ntshav qab zib raum, thiab kab lis kev cai podocytes tiv thaiv oxidative puas thiab glomerulosclerosis. Analogously, stimulation nrog metformin los yog AICAR, (ob qho tib si ua kom AMPK) los yog resveratrol txo lub raum qhia ntawm pro-fibrotic TGF 1 thiab alpha-smooth nqaij actin (SMA).91, 92, 111, 112 Kuj tseem muaj pov thawj los ntawm cov nas mob ntshav qab zib. thiab kab lis kev cai podocytes uas PGC1 qhia tau txhawb nqa qhov kev qhia ntawm cov noob tseem ceeb podocyte, nephrin, thiab podocalyxin, uas tswj kev pom kev tsis sib haum xeeb.107, 113 Hauv hom 2 mob ntshav qab zib nas qauv, hyperglycemia kuj tau coj mus rau tsub zuj zuj ntawm lipids hauv cov ntshav qab zib raum 114 nrog cov txiaj ntsig zoo. thiab oxidative kev nyuaj siab uas tau ntev tau txuam nrog DKD progression.115 Diabetic nas tau txais fenofibrate, ib tug PPAR agonist, nthuav tawm nce AMPK, PGC1, thiab PGC1 lub hom phiaj gene qhia; Cov kev hloov no tau cuam tshuam nrog txo qis albuminuria, lub raum fatty acid tsub zuj zuj, mesangial expansion, thiab inflammatory infiltrate.114 Sab nraum DKD, lub luag hauj lwm tiv thaiv ntawm PGC1 nyob rau hauv nephrotic syndrome yog ib qho zoo siab tshiab lub sijhawm uas tsuas yog pib kawm. Hauv cov nas, kev kho pioglitazone hauv FSGS qauv tiv thaiv glomerulosclerosis.116 Thiab, raws li qhia hauv cov kev tshawb fawb hyperglycemia, ua kom PGC1 txoj hauv kev txo qis proteinuria nrog nce kev qhia ntawm nephrin thiab synaptopodin hauv ib qho mob nephrotic syndrome nas model.117 Cov ntaub ntawv cog lus tshaj plaws txog PGC1. Lub hom phiaj cov noob ameliorating nephrosis los ntawm kev sim ntawm PPAR agonists hauv cov neeg mob nephrotic syndrome. Nyob rau theem kuv sim ntawm rosiglitazone, tsib ntawm kaum ib tus neeg mob uas muaj thawj focal segmental glomerulosclerosis (FSGS) tau ncua kev ua haujlwm ntawm lub raum tsis zoo nyob rau lub sijhawm 16-hli lub sijhawm rov qab los piv rau kev kho ua ntej.118 Tsis ntev los no, Muaj cov xwm txheej tshwm sim ntawm cov menyuam yaus uas muaj cov kab mob steroid-resistant nephrotic uas nws tus kab mob tau teb rau pioglitazone therapy.119 Nrog cov ntaub ntawv DKD thiab nephrotic syndrome hauv siab, tus qauv nas ntawm podocyte-specific PGC1 overexpression tau tsim. Kuj ceeb tias, PGC1 overexpression coj mus rau albuminuria, azotemia, thiab histology raws li kev sib tsoo FSGS uas yog gene-dose teb. PGC1 overexpression kuj hloov lub podocyte lub zog nyiam los ntawm cov piam thaj mus rau fatty acid oxidation.120 Nws tsis paub meej tias vim li cas PGC1 stimulation tsis ncaj los ntawm kev ua kom cov dej ntws los ntawm cov neeg tswj hwm los yog agonism ntawm PGC1 downstream phiaj, PPAR, yog kev tiv thaiv ntawm podocyte kev noj qab haus huv thaum direct transgenic overexpression yog detrimental. . Tseem muaj ntau yam yuav tsum tau kawm, tab sis muaj kev cia siab tias tsawg kawg yog qee lub hom phiaj hauv PGC1 txoj hauv kev tuav cov lus cog tseg rau kev kho mob glomerular.
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