Clinicopathological Relvance Ntawm PAX8 Kev Qhia Txog Tus Qauv Hauv Kev Mob Raum Mob Thiab Kab Mob Raum Ntev
Oct 30, 2023
3.2. Kab mob raum
Yog tus cwj pwm los ntawm Greater Fission thiab Tsawg Fusion ntawm Mitochondria.Mitochondrial fragmentationyog ib tug raug pathological feature ntawm mob thiabmob raum mob, uas txhais tau tias muaj ib qho iimbalance nyob rau hauv lub fission thiab fusion ntawm mitochondriahauvkab mob raum. Kev ua kom tsis zoo ntawm Drp1 thiab covinhibition ntawm Mfn2 yog qhov tseem ceeb ua rau ntau tshaj mitochondrial fission hauv cov kab mob.. Qhov no mitochondrial fission induces apoptosis los ntawm activating proapoptotic protein Bax, uas ua rau ntxiv raum puas [41]. Brooks et al. [42] soj ntsuam cov teebmeem ntawm mitochondrial dynamics ntawm AKI siv cov qauv ntawm ischemic thiab cisplatin-induced AKI nyob rau hauv nas proximal tubular hlwb thiab thawj proximal tubular hlwb cais los ntawm C57BL/6 nas. Lawv tau pom tias cov mitochondrial fragmentation ntau heev thaum lub sijhawm pib ntawm AKI yog txuam nrog kev ua haujlwm siab Drp1 thiab qhov inhibition ntawm Drp1 siv cov caj ces lossis cov tshuaj pharmacological kom txo tau cytochrome C tso tawm, caspase activation, thiab tubular cell apoptosis. Tsis tas li ntawd, siv nyob rau hauv vivo qauv ntawm lub raum ischemia / reperfusion raug mob, Perry li al. [43] pom tias Drp1 tsis txaus ua rau muaj kev nthuav qhia ntawm Ki67, ib qho antigen cuam tshuam nrog cov cell proliferating, thiab PGC-1, uas txo cov ntshav creatinine concentration thiab ameliorates tubular atrophy, implying hais tias inhibition ntawm Drp1 txhawb kev puas tsuaj nyob rau hauv cov ntshav. lub raum. Tsis tas li ntawd, Wang et al. [44] siv lub unilateral ureteral obstruction kev phais-vim tus qauv ntawm fibrosis thiab ib txwm nas raum fibroblast hlwb (NRK-49F) los qhia tias cov mitochondrial fission ntau tshaj uas yog kho los ntawm phosphorylated Drp1 koom rau hauv kev hloov ntawm fibroblasts rau hauv myofibroblasts. Hauv kev raug mob raum los ntawm kev nce qib fibrin thiab txhawb nqa glycolysis. Yog li, ntau tshaj mitochondrial fission pab txhawb kev loj hlob ntawm cov mob fibrosis. Ntxiv mus, Ayanga et al. [45] qhia tau hais tias qhov knockout ntawm Drp1 protein nyob rau hauv podocytes ntawm cov nas mob ntshav qab zib muaj cov nyhuv renoprotective los ntawmtxo cov proteinuria,txhim kho mitochondrial muaj nuj nqi, thiabtxo mitochondrial kev puas tsuajthiabkev raug mob podocyte.
Hauv kab mob, kev tswj tsis zoo ntawm Mfn2 proteins tsis yog xwbnce mitochondrial fissiontab sis kuj tseem cuam tshuam mitochondrial fusion, uas muaj kev cuam tshuam loj heev rau lub zog thiab cov khoom noj metabolism ntawm tus kheej mitochondria [46]. Tsis tas li ntawd, Gall et al. [47] pom tau tias Mfn2 deficiency nyob rau hauv proximal tubular epithelial hlwb muaj peev xwm nce cellular apoptosis nyob rau hauv lub xeev ntawm kev nyuaj siab, uas yog yus muaj los ntawm ATP depletion. Tsis tas li ntawd, Brooks et al. [48] pom tias apoptotic protein Bax yog qhib los ntawm mitochondrial fission thiab exacerbates raum raug mob. Siv cov qauv hauv vitro ntawm cisplatin- thiab azide-induced AKI, lawv pom tias overexpression ntawm mitofusins los yog inhibition ntawm Drp1 txo cytochrome C tso tawm los ntawm mitochondria thiab apoptosis los ntawm kev thaiv kev nkag ntawm Bax rau hauv OMM. Ntxiv mus, qhov inhibition ntawm mitofusins tau pom tias nce cisplatin-induced Bax activation, tso tawm ntawm cytochrome C, thiab apoptosis. Hauv cov ntsiab lus, ntau tshaj mitochondrial fission txhawb rau lub raum kev puas tsuaj nyob rau hauv ob qho tib si mob raum thiab mob raum raug mob, uas txhais tau hais tias inhibition ntawm ntau tshaj mitochondrial fission yuav sawv cev rau lub hom phiaj kho mob raum kab mob.
NYEEM NTXIV RAU HAUV PAUS TSEEM CEEB NTAWM CISTANCHE FOR KIDNEY
3.3. Kab mob raum yog yam ntxwv los ntawm Dysfunctional Mitophagy. Txhawm rau ua kom tau raws li qhov xav tau ntawm lub zog siab, lub raum yog nplua nuj nyob hauv mitochondria. Txawm li cas los xij, mitochondria yog qhov ua rau muaj kev hloov pauv hauv lawv cov DNA thiab organelle puas. Yog li ntawd, txhawm rau kom noj qab haus huv mitochondrial homeostasis, nws yog ib qho tsim nyog yuav tau tshem tawm mitochondria puas los ntawm mitophagy. Lei et al. [49] pom tias tus inducer ntawm mitophagy, rapamycin, ameliorates raug mob nyob rau hauv HK-2 hlwb, whereas 3-methyladenine, ib tug inhibitor ntawm mitophagy, ua phem rau qhov raug mob. Txawm li cas los xij, Zhao et al. [50] pom ob qho tib si hauv vitro thiab hauv vivo tias glycoprotein stanniocalcin -1 (STC1) (ib tug paub mitochondrial-targeted antioxidant) inhibits lub raum raug mob nyob rau hauv sib piv rau tus neeg saib xyuas-induced AKI, tab sis hais tias qhov no yog nrog los ntawm ib tug txo nyob rau hauv mitophagy. , uas tsis sib haum nrog cov kev tshawb pom yav dhau los. Cov kws sau ntawv tau xav tias STC1 kev kho ua ntej ua rau muaj qhov qis ntawm mitophagy, uas qhia txog cov txiaj ntsig ntawm STC1 ntawm kev raug mob mitochondrial, raws li lub hauv paus ntsiab lus tias mitophagy yog pib los ntawm kev raug mob mitochondrial. Yog li, hauv cov ntsiab lus, kev nce hauv mitophagy pab kho qhov kev tshem tawm ntawm kev puas tsuaj mitochondria thaum lub raum raug mob.
Ib tug xov tooj ntawm txoj kev taw qhia uas tswj mitophagy, suav nrog PINK1 / Parkin, BNIP3, thiab Drp1 txoj hauv kev, tau pom los txhawb kev kho mob raum hauv AKI. Ua ntej, qhov tsis txaus ntawm PINK1 thiab Parkin tau pom tias ua rau mob hnyav rau hauv cov nas los ntawm inhibiting mitophagy thiab ua kom cov mitochondrial puas tsuaj [51]. Tsis tas li ntawd, PINK1 / Parkin-mediated mitophagy tau raug pom los tiv thaiv AKI vim yog cisplatin, sepsis, lossis tus neeg sawv cev sib txawv [52–54]. Thib ob, Tang et al. [55] tau qhia txog kev tiv thaiv lub raum ntawm BNIP3-kev kho mob mitophagy hauv nas qauv ntawm lub raum ischemia/reperfusion raug mob. Lawv tau pom tias shRNA-induced silencing ntawm BNIP3 nyob rau hauv kab lis kev cai raum tubular hlwb txo mitophagy thiab potentiates cell tuag thiab hais tias BNIP3 knockout nyob rau hauv nas ua rau lub raum tsis ua hauj lwm thiab cov ntaub so ntswg puas, uas paub meej tias BNIP3 muaj ib tug tseem ceeb luag hauj lwm nyob rau hauv mitophagy thiab cell ciaj sia. Thaum kawg, Li et al. [56] pom tias kev kho mob ua ntej nrog mdivi-1, ib qho inhibitor ntawm Drp1, impairs mitophagy thiab ua rau lub raum tsis ua haujlwm thiab tubular cell apoptosis nyob rau hauv tus qauv ntawm lub raum ischemia / reperfusion raug mob. Cov kev tshawb fawb yav dhau los kuj tau qhia tias kev puas tsuaj mitophagy thiab cov khoom ntawm cov kab mob mitochondria puas ua rau cov txheej txheem kev laus thiab kev loj hlob ntawm cov hnub nyoog ntsig txog kab mob raum [57]. Tsis tas li ntawd, cov kab mob mitophagy hauv podocytes pab txhawb kev mob ntshav qab zib nephropathy. Fang et al. [58] pom tias ntshav qab zib hauv vivo thiab cov piam thaj ntau hauv vitro cuam tshuam nrog kev ua haujlwm tsis zoo hauv autophagy hauv podocytes, uas txhawb kev raug mob ntawm tes thiab ua kom cov ntshav qab zib nephropathy nce ntxiv. Tom qab ntawd, siv streptozotocin-induced ntshav qab zib nas thiab nas podocyte kab kab lis kev cai nyob rau hauv nruab nrab-qabzib siab, Li li al. [59] tau qhia tias forkhead-box class O1 (FoxO1) txhawb nqa kev kho mob podocyte thiab ncua kev mob ntshav qab zib nephropathy los ntawm inducing PINK1 / Parkin-mediated mitophagy. Yog li ntawd, hauv cov ntsiab lus, kev txhawb nqa ntawm mitophagy hauv kev mob raum mob thiab mob ntev tuaj yeem yog cov txiaj ntsig kho mob.
3.4. Deficiency ntawm Mitochondrial Biogenesis hauv raum Kab Mob.
Mitochondrial biogenesis yog qhov tseem ceeb rau kev kho cov cellular puas hauv AKI. PGC-1 yog qhov tseem ceeb tshaj plaws ntawm kev hloov pauv ntawm mitochondrial biogenesis thiab yog li ntawd feem ntau tau kawm thaum tshawb fawb txog lub luag haujlwm ntawm mitochondrial biogenesis hauv kev kho lub raum. Piv txwv li, Rasbach thiab Schnellmann [60] tau kho lub raum lub raum tubular cov hlwb cais tawm los ntawm cov luav siv T-butyl hydroperoxide los ntxias hom mitochondrial dysfunction uas cuam tshuam nrog ischemia / reperfusion raug mob thiab pom tias sublethal cell puas raug kho li ntawm 6 hnub. Thaum lub sij hawm tus txheej txheem no, cov lus qhia ntawm PGC-1 tau nce ntau nyob rau hauv 24 teev thiab tau khaws cia nyob rau theem siab kom txog thaum rov ua tiav, uas qhia tias PGC-1 -kuaj kho mitochondrial biogenesis ameliorates raum raug mob thiab txhawb kev puas tsuaj. Hauv kev ua haujlwm tom ntej, pab pawg no tau qhia ntxiv lub luag haujlwm ntawm PGC-1 hauv kev txhawb nqa kev kho kev puas tsuaj los ntawm overexpressing PGC-1 ua ntej raug oxidants [5]. Lawv pom tias qhov no tsis tau khaws cia mitochondrial muaj nuj nqi tab sis hloov pauv, muaj peev xwm ua haujlwm tsis zoo thiab kev tuag ntawm tes, uas tuaj yeem piav qhia los ntawm kev nce hauv mitochondrial biogenesis thaum lub sij hawm raug mob tsim kom muaj cov mitochondria puas, uas yuav ua rau qhov raug mob hnyav dua. Txawm li cas los xij, nce qhov kev nthuav qhia ntawm PGC-1 tom qab oxidant raug ua rau nrawm nrawm ntawm cov hlwb, tej zaum vim tias nyob rau theem no muaj qhov xav tau ntau rau kev tsim kho mitochondria los pab txhim kho cov txheej txheem kho.
Funk ib Schnellmann [61] tau kawm txog lub luag haujlwm ntawm mitochondrial biogenesis hauv tsiaj qauv ntawm myoglobinuric AKI thiab ischemic AKI. Hauv ob qho tib si qauv, cov qauv thiab kev ua haujlwm ntawm lub raum tubules raug cuam tshuam, tab sis muaj qee qhov rov ua haujlwm ntawm glomerular. Cov lus qhia ntawm PGC-1 tau siab heev thaum lub sij hawm thaum ntxov ntawm kev thuam thiab tseem nyob siab nyob rau hauv txoj kev kho. Txawm li cas los xij, qhov kev qhia ntawm mitochondrial respiratory proteins yog tsawg heev thaum lub sij hawm thaum ntxov thiab tsis rov qab mus txog rau theem tom qab ntawm kev kho. Yog li, PGC-1 qhia tau nce sai sai tom qab pib ntawm AKI, tab sis nws cov kev hloov pauv tau cuam tshuam los ntawm kev ua rau muaj mob tsis tu ncua, uas ua rau muaj kev puas tsuaj mitochondrial thiab kho tsis zoo. Los ntawm qhov sib txawv, qhov kev qhia ntawm PGC-1 yog downregulated nyob rau hauv folic acid-induced thiab sepsis-associated AKI, thiab lub overexpression ntawm PGC-1 ameliorates lub deleterious teebmeem ntawm ob insults [62, 63]. Tsis tas li ntawd, Fontecha-Barriuso et al. [64] pom tau tias PGC-1 deficiency ua rau muaj kev raug mob ntawm tes los ntawm inhibiting mitochondrial biogenesis thiab nce o hauv tus nas qauv ntawm folic acid-induced AKI.
Hauv cov ntsiab lus, txawm tias qib ntawm PGC-1 qhia txawv raws li hom AKI, nce nws cov haujlwm pab kho kev puas tsuaj hauv AKI. Txawm li cas los xij, qhov cuam tshuam ntawm mitochondrial biogenesis nyob rau hauv cov kab mob raum ntev tsis yog universal. Kev tshaj tawm lossis kev siv tshuaj tshuaj ntau dhau ntawm PPAR yog ib txoj hauv kev zoo ntawm kev txhawb nqa PGC-1 . Hauv db/db mob ntshav qab zib nas, nas podocytes, thiab lub raum mesangial hlwb kab lis kev cai nyob rau hauv ib tug high-glucose nruab nrab, PPAR agonist rosiglitazone muaj cov teebmeem renoprotective, ameliorating oxidative kev nyuaj siab, glomerulosclerosis, thiab tubulointerstitial fibrosis los ntawm kev nthuav qhia PGC {5{3} ]. Lwm txoj kev tshawb fawb kuj tau pom tias lub raum fibrosis hauv cov nas mob ntshav qab zib yog inhibited los ntawm kev tshuaj ntsuam genetic lossis pharmacological activation ntawm PPAR [66]. Txawm hais tias PGC-1 tau raug tshaj tawm tias muaj kev tiv thaiv hauv feem ntau cov kev tshawb fawb ntawm CKD, Li et al. [7] pom tias PGC ntau dhau -1 nce proteinuria thiab ua rau lub raum tsis ua haujlwm hauv cov nas mob ntshav qab zib nrog podocyte tshwj xeeb overexpression ntawm PGC-1 . Tsis tas li ntawd, PGC-1 overexpression kuj tau pom tias ua rau poob ntawm cov qauv sarcomeric thiab dilated cardiomyopathy hauv cardiomyocytes [67]. Txawm hais tias nws tsis to taub tag nrho, cov txheej txheem ntawm cov teebmeem tsis zoo ntawm PGC-1 nyob rau hauv cov kab mob ntev yuav cuam tshuam nrog kev txhawb nqa ntawm angiogenesis tom qab ischemia vim tias cov txheej txheem no ua rau muaj kev puas tsuaj rau ischemic thiab hypoxic rau cov hlwb hauv lub raum, uas txhawb nqa. fibrosis [68].
4. Lub luag haujlwm ntawm Nrf2 Ua kom muaj kev tswj hwm ntawm Mitochondrial Homeostasis hauv raum Kab Mob
4.1. Ischemia/Reperfusion-Induced AKI.
Lub raum ischemia / reperfusion raug mob (RIRI) yog ib qho teeb meem loj ntawm kev mob hnyav thiab kev phais mob uas cuam tshuam nrog kev ua haujlwm tsis zoo rau thawj tus kab mob thiab muaj peev xwm tseem ceeb ntawm AKI-txuas nrog kev tuag [69]. Lub pathogenesis ntawm RIRI cuam tshuam nrog ischemic/hypoxic raug mob rau proximal tubular thiab endothelial hlwb [70]. Ischemia-txog hypoxia ua rau lub raum puas thiab microvascular dysfunction los ntawm inflammatory thiab oxidative kev nyuaj siab cascades, ua rau hypoxic raug mob thiab ROS tsub zuj zuj nyob rau hauv lub raum. Thaum lub sijhawm ua haujlwm no, cov khoom siv oxygen thiab kev xav tau cuam tshuam loj heev los ntawm cov ntshav qis mus rau lub raum medulla, uas cuam tshuam rau kev thauj mus los. Tom qab ntawd, reperfusion yog txuam nrog kev txhawb nqa kev thauj mus los uas tsis tuaj yeem ua kom yooj yim los ntawm qib ntawm reoxygenation, uas ua rau cov pa oxygen tsis txaus, ua rau ntxiv ROS ntau ntxiv thiab mob raum [71]. Cov txheej txheem pathophysiological ntawm RIRI kuj suav nrog kev raug mob mitochondrial, apoptosis, necrosis, thiab o, uas mitochondrial raug mob plays lub luag haujlwm tseem ceeb [72]. Qhov hnyav oxygen tsis txaus thiab oxidative kev nyuaj siab uas tshwm sim los ntawm hypoxia thiab reoxygenation hnyav cuam tshuam rau mitochondrial homeostasis. Nrf2 yog qhov tseem ceeb tshaj plaws ntawm cov tshuaj tiv thaiv antioxidant thiab tau pom tias ua lub luag haujlwm tiv thaiv tseem ceeb hauv RIRI. Leonard et al. [73] pom thawj zaug uas siv microarray tsom xam tias qhov kev qhia ntawm Nrf2 thiab Nrf2- -dependent antioxidative genes induced as an adaptive mechanism to reduce renal cellular damage in a model of ischemia/reperfusion. Lawv kuj tau qhia tias qhov kev tshem tawm ntawm Nrf2 ua rau muaj kev cuam tshuam ntawm nas rau RIRI thiab kev kho antioxidant tiv thaiv lub raum puas, yog li lees tias Nrf2 ameliorates RIRI los ntawm inducing ib qho antioxidant teb [74]. Zhang et al. [75] tau kawm txog qhov cuam tshuam ntawm simvastatin ntawm RIRI hauv cov nas thiab pom tias nws muaj lub luag haujlwm tiv thaiv kev sib haum xeeb los ntawm kev ua kom Nrf2/ HO-1 thiab kho dua ntawm redox homeostasis. Tsis tas li ntawd, Nezu et al. [76] pom tau tias Nrf2 tiv thaiv RIRI-vim lub raum puas tsuaj siv Nrf2 thiab Keap1 knockdown nas, qhia tias Nrf2 muaj txiaj ntsig zoo rau redox xwm txheej, mitochondrial biogenesis, thiab cell proliferation. Tsis tas li ntawd, lawv tau txiav txim siab seb lub sijhawm ua kom Nrf2 yog qhov tseem ceeb los ntawm pharmacologically activating Nrf2 thaum ntxov lossis lig theem ntawm kev thuam. Lawv pom tias Nrf2 ua rau lub sijhawm thaum ntxov, tab sis tsis yog theem kawg, ua kom lub raum raug mob. Yog li, qhov ua kom ntxov ntxov ntawm Nrf2 zoo li tseem ceeb hauv kev ua kom qeeb ntawm kev mob raum tubular.
4.2. Septic AKI.
Sepsis yog ib qho kev kho mob uas tshwm sim los ntawm cov kab mob kab mob thiab ua rau cov kab mob inflammatory thiab feem ntau ua rau ntau lub cev tsis ua hauj lwm, nrog rau lub raum tsis ua hauj lwm, uas yog hu ua septic mob raum raug mob (SAKI). Hauv cov neeg mob hauv chav saib xyuas mob hnyav, SAKI yog ib qho teeb meem loj uas yog tus cwj pwm los ntawm kev mob hnyav, kev tuag siab, thiab kev ua tsis zoo [77]. Hauv cov neeg mob zoo li no, kev kho cov kab mob tua kab mob thiab hemodialysis los kho uremia tsis txo qis qhov tshwm sim ntawm kev tuag los yog qhov tshwm sim ntev ntawm CKD [78]. Yog li ntawd, nws yog ib qho tseem ceeb kom paub ntxiv txog qhov pathogenesis ntawm SAKI txhawm rau txheeb xyuas cov kev kho mob zoo dua.
Kev tshawb fawb los ntawm Takasu et al. [79] pom tias muaj kev tsis sib haum xeeb ntawm lub raum tsis ua haujlwm thiab kev puas tsuaj ntawm cov neeg mob SAKI. Lawv pom tias feem ntau ntawm cov neeg mob sepsis muaj qhov raug mob tubular, tab sis cov kev raug mob no kuj yog me me, xws li cov kab mob focal los yog qhov chaw me me ntawm necrosis, thaum thaj chaw loj ntawm tubular raug mob lossis tubular necrosis tsis tshua muaj, uas tsis sib haum nrog qhov hnyav. lub raum tsis ua haujlwm hauv cov neeg mob no. Tsis tas li ntawd, cov yam ntxwv ntawm cov txheej txheem ntawm qhov raug mob feem ntau yog mitochondrial o, lysosomal expansion, thiab ntau dua autophagy. Yog li, qhov mob raum mob me me hauv cov neeg mob SAKI tsis tuaj yeem piav qhia txog lub raum tsis ua haujlwm hnyav. Txawm li cas los xij, cov yam ntxwv ntawm kev raug mob mitochondrial uas tau txheeb xyuas hauv txoj kev tshawb no yog ua raws li kev qhia yav dhau los ntawm kev txhim kho hauv SAKI uas tuaj yeem ua tiav los ntawm kev txhim kho ntawm mitochondrial biogenesis [62], thiab cov txiaj ntsig ntawm ob qho kev tshawb fawb no qhia tias kev ua haujlwm ntawm mitochondrial ua lub luag haujlwm tseem ceeb. nyob rau hauv lub pathogenesis ntawm SAKI.
Cov teebmeem ntawm Nrf2 nyob rau hauv mitochondrial homeostasis thiab nws cov kev tiv thaiv nyob rau hauv ib tug qauv ntawm SAKI prompted ntxiv kev tshawb fawb ntawm lub luag hauj lwm ntawm Nrf2 nyob rau hauv mitochondrial homeostasis nyob rau hauv SAKI thiab lub mechanism ntawm kev koom tes. Ntau qhov kev tshawb fawb tau pom tias Nrf2 ameliorates SAKI los ntawm kev tswj cov mitochondrial redox homeostasis thiab txo oxidative kev nyuaj siab hauv hlwb thiab mitochondria [80–82]. Kev taw qhia ntawm tib neeg glomerular qaum cov ntshav mononuclear hlwb rau hauv cov qauv nas ntawm SAKI muaj cov nyhuv renoprotective los ntawm kev ua kom Nrf2, yog li txhawb nqa mitophagy [83], thiab qhov no sawv cev rau kev cog lus tshiab kho tshiab. Kev tshawb fawb los ntawm Liu et al. [84] pom tias qhov ua kom Nrf2 los ntawm cov tshuaj tiv thaiv antioxidant procyanidin B2 ameliorates lub raum raug mob thiab tubular cell apoptosis hauv nas nrog SAKI los ntawm kev txhim kho mitochondrial dynamics thiab nce mitophagy. Tshwj xeeb, Gonzalez et al. [4] pom tau hais tias qhov kev rov qab los ntawm mitochondrial dynamics yog qhov tseem ceeb hauv kev daws teeb meem ntawm septic organ tsis ua hauj lwm los ntawm kev kawm ob qho qauv ntawm sepsis: endotoxemia induced los ntawm lipopolysaccharide (LPS) thiab cecal ligation thiab puncture (CLP). Lawv tau pom tias qhov kev tuag ntawm CLP muaj ntau dua li qhov cuam tshuam nrog endotoxemia, thiab ua raws li qhov no, kev rov qab los ntawm mitochondria hauv CLP yog qhov phem dua li hauv endotoxemia. Tsis tas li ntawd, nyob rau hauv endotoxemia, ib qho kev puas tsuaj ntawm mitochondrial dynamics tsim sai sai tom qab qhov pib, tab sis qhov no pib daws tom qab 24 teev, qhov mitochondrial biogenesis tsis pib hauv 24 teev. Hloov chaw, qhov kev puas tsuaj loj rau mtDNA tau pib rov zoo tom qab 48 teev. Yog li ntawd, lawv tau txiav txim siab tias kev rov zoo los ntawm cov kab mob septic tsis ua haujlwm yog nyob ntawm kev kho thaum ntxov ntawm mitochondrial dynamics, es tsis yog ntawm mitochondrial biogenesis, thiab qhov no yog corroborated los ntawm qhov tseeb tias pretreatment nrog mdivi -1 (ib tug Drp1 inhibitor) ho ameliorates mitochondrial. Kev ua haujlwm tsis zoo thiab apoptosis hauv CLP.
4.3. Drug-Induced AKI.
Hauv kev kho mob, ntau cov tshuaj uas tawm hauv lub raum, xws li tshuaj antineoplastic, tshuaj tua kab mob, thiab cov tshuaj sib txawv, tuaj yeem ua rau mob raum tsis ua haujlwm, ib yam mob hu ua tshuaj tua kab mob AKI. Perazella thiab Luciano [85] tau npaj cov ncauj lus kom ntxaws txog cov tshuaj uas tuaj yeem ua rau lub raum raug mob, suav nrog hom hemodynamic, vascular, glomerular, thiab tubulointerstitial hom. Feem ntau, kev kho cov tsos mob, xws li tshem tawm cov tshuaj nephrotoxic thiab kev tswj hwm ntawm corticosteroid, yog txaus kom tso cai kom rov zoo tag nrho los ntawm kev siv tshuaj AKI. Txawm li cas los xij, kev tswj tau zoo ntawm kev kho mob thiab nephrotoxic cuam tshuam ntawm cov tshuaj nephrotoxic thaum lawv tsis tuaj yeem tshem tawm tseem yog qhov nyuaj rau cov kws kho mob, thiab qhov no yog qhov laj thawj tseem ceeb vim li cas cov kws tshawb fawb txuas ntxiv lawv cov kev siv zog kom nkag siab txog cov kab mob ntawm cov tshuaj tua kab mob AKI thiab tsim cov tshuaj renoprotective tshwj xeeb. . Ib yam li lwm hom kev raug mob raum, mitochondrial dysfunction thiab qis Nrf2 kev ua haujlwm tau koom nrog hauv cov kab mob ntawm cov tshuaj tua kab mob AKI. Cisplatin yog siv dav thiab siv tau zoo chemotherapeutic tus neeg saib xyuas, tab sis nws muaj ntau yam kev mob tshwm sim, suav nrog nephrotoxicity, uas yog ib qho teeb meem loj uas cuam tshuam nrog kev mob tsis zoo [86]. Cisplatin yog ib qho zoo electrophilic reagent nyob rau hauv cov hlwb, thiab tshwj xeeb tshaj yog nyob rau hauv lub tubular epithelial hlwb ntawm lub raum, xws li hais tias nws tshwj xeeb accumulates nyob rau hauv lub mitochondria tsis zoo, uas yuav induce loj cheeb tsam ntawm mitochondrial puas, ua rau nws kim heev mitophagy thiab tej zaum ib tug malignant tshwm sim. [87]. Yog li, nyob rau hauv cisplatin-induced lub raum raug mob, cov tswv yim tsom rau ameliorating mitochondrial kev puas tsuaj thiab suppressing mitophagy ntau pab txhawb rau kev cawm ntawm ib txwm mitochondria thiab kev txuag ntawm cellular muaj nuj nqi. Nrf2 tau pom tias inhibit cytochrome C tso tawm thiab apoptosis hauv cisplatin-induced apoptotic HK{11}} hlwb, uas txhais tau hais tias nws ua lub luag haujlwm tseem ceeb hauv kev tswj hwm mitochondrial kev ncaj ncees thiab kev ua haujlwm [88]. Tsis tas li ntawd, Nrf2 activation tau pom tias muaj kev tiv thaiv hauv lub raum, los ntawm kev tswj cov redox homeostasis hauv mitochondria, hauv vivo qauv ntawm cisplatin-induced AKI [89]. Nyob rau hauv sib piv rau cisplatin-induced AKI, ntau dua mitophagy tau pom tias ameliorate lub raum raug mob nyob rau hauv sib piv tus neeg saib xyuas-induced AKI, whereas mitophagy qis exacerbated qhov raug mob [49]. Hauv lwm txoj kev tshawb fawb, nws tau pom tias cov tshuaj preconditioning ntawm STC1 tiv thaiv qhov sib txawv-induced AKI los ntawm modulating mitochondrial dynamics thiab txo mitochondrial kev puas tsuaj, xws li muaj tsawg mitophagy [50]. Raws li qhov xwm txheej tau teev tseg saum toj no, ob qhov kev tshawb pom no tsis yog qhov tsis sib xws, thiab tom kawg qhia txog lub luag haujlwm tseem ceeb ntawm Nrf2 ua kom muaj kev tswj hwm ntawm mitochondrial homeostasis thiab kev tiv thaiv ntawm mitochondria, nrog rau cov txiaj ntsig zoo ntawm kev kho mob thaum ntxov rau kev khaws cia ntawm mitochondria. thiab txhawb kev rov qab los ntawm lub raum raug mob.
4.4. Mob ntshav qab zib raum (DKD). DKD, tseem hu ua mob ntshav qab zib nephropathy, yog cov kab mob uas tau kawm tshaj plaws nrog rau kev tiv thaiv los ntawm Nrf2 ua rau hauv CKD. DKD yog ib qho teeb meem loj thiab mob hnyav ntawm cov ntshav qab zib, nrog rau qhov ua rau loj ntawm CKD thiab ESRD, thiab nws yog tus cwj pwm los ntawm lub raum ua haujlwm tsis zoo, cov proteinuria loj heev, thiab mob raum fibrosis. Cov yam ntxwv thaum ntxov ntawm DKD yog glomerular raug mob nrog mesangial dilation, hauv qab daus membrane thickening, thiab podocyte poob; thiab cov no yog ua raws li kev puas tsuaj rau lub raum tubules thiab interstitium, xav txog hauv tubular hauv qab daus daim nyias nyias nyias, tubular atrophy, interstitial fibrosis, thiab arteriosclerosis [90]. Cov txheej txheem pathophysiological ntawm DKD cuam tshuam nrog hyperglycemia, kev puas tsuaj rau lub raum hauv lub raum, thiab cov hemodynamics txawv txav. Kev puas tsuaj rau glomerular filtration barrier uas yog tshwm sim los ntawm kev raug mob podocyte ua rau cov protein ntau nkag mus rau hauv cov zis hauv DKD. Tsis tas li ntawd, kev puas tsuaj rau mesangial thiab endothelial hlwb ua rau hemodynamic txawv txav uas muaj xws li dilation ntawm afferent arterioles thiab lub raum vasoconstriction, nrog rau cov proteinuria thiab cov piam thaj tsis zoo metabolism, uas ua rau oxidative kev nyuaj siab thiab mitochondrial puas nyob rau hauv lub raum hlwb [91].
Nrf2 tau pom tias ua lub luag haujlwm tiv thaiv hauv kev sim kev tshawb fawb ntawm DKD, kho los ntawm nws cov teebmeem antioxidant thiab cov teebmeem ntawm mitochondrial homeostasis. Kev kawm los ntawm Jiang.
Bardoxolone methyl (BARD), tus activator ntawm Nrf2, tau sim thawj zaug hauv theem kuv kuaj mob qog noj ntshav, uas Nrf2 ua kom pom tau zoo txhim kho qhov kwv yees glomerular filtration rate (eGFR) [94]. Txawm li cas los xij, hauv kev sim tshuaj tom ntej tau ua rau cov neeg mob uas muaj hom 2 mob ntshav qab zib mellitus thiab theem 4 CKD (theem 3 BEACON txoj kev tshawb fawb), thiab txawm tias muaj kev txhim kho hauv eGFR, BARD tau cuam tshuam nrog ntau dua proteinuria thiab mob plawv plawv, uas ua rau kev txiav tawm ntxov ntxov. kev sim [95]. Tom qab ntawd, Rush et al. [96] kuj tau qhia tias Nrf2 ua kom cov nas tuaj yeem ua rau CKD ua rau hnyav dua. Txhawm rau txiav txim siab seb kev siv BARD hauv cov neeg mob DKD puas cuam tshuam nrog kev saib xyuas eGFR, theem 2 TSUBAKI txoj kev tshawb fawb tau ua rau cov neeg mob ntshav qab zib thiab theem 3 CKD [97], thiab qhov kev tshawb pom ua ntej yog tias BARD tau txhim kho eGFR yam tsis tau nce ntxiv. qhov xwm txheej ntawm cov kab mob plawv. Cov kev tshawb fawb no qhia tias Nrf2 ua kom muaj txiaj ntsig zoo thiab muaj kev nyab xeeb thaum lub sijhawm ntxov ntawm CKD tab sis tuaj yeem ua rau muaj kev pheej hmoo ntawm cov xwm txheej tsis zoo thaum lub sijhawm lig. Yog li, Nrf2 ua kom muaj peev xwm kho tau hauv cov neeg mob CKD, tab sis lub sijhawm ntawm kev tswj hwm yuav yog tus yuam sij rau nws txoj kev siv tau zoo.
5. Cov lus xaus
Feem ntau, txoj kev loj hlob ntawm AKI tuaj yeem muab faib ua peb theem: kev raug mob thaum ntxov, kev raug mob hnyav, thiab rov qab los ntawm qhov raug mob [61]. Nrog rau kev hloov pauv ntawm ib puag ncig pathophysiological thaum lub sijhawm AKI, cov xwm txheej mitochondrial uas cuam tshuam rau kev loj hlob ntawm kev rov qab los ntawm tus kab mob hloov. Nyob rau theem pib ntawm AKI, kev ua kom muaj kev sib tsoo thiab kev puas tsuaj ntawm fusion ntawm mitochondria ua rau muaj kev puas tsuaj loj thiab kev ua haujlwm tsis zoo, uas ua rau muaj kev puas tsuaj hauv mitochondrial zog tiam thiab apoptosis. Yog li ntawd, kev txhim kho nyob rau hauv mitochondrial dynamics thaum lub sij hawm thaum ntxov ntawm kev raug mob plays lub luag hauj lwm txiav txim nyob rau hauv rov qab [4]. Tom qab ntawd, mitophagy yog upregulated raws li tus naj npawb ntawm puas thiab puas mitochondria nce. Nyob rau theem no, cov xwm txheej redox, mitochondrial dynamics, thiab mitochondrial biogenesis cuam tshuam rau kev loj hlob ntawm qhov raug mob [76, 84]. Hloov pauv, kev hloov pauv ntawm mitochondrial biogenesis tuaj yeem raug tshem tawm thaum lub sijhawm ntxov, nrog kev nce ntawm cov mitochondria tsis paub qab hau uas ua rau ntau tus mitochondria puas, yog li ua rau qhov tsis xws luag [5]. Ib yam uas paub tseeb yog tias mitochondrial biogenesis muaj lub luag haujlwm tiv thaiv kev txiav txim siab thaum rov qab los ntawm kev raug mob [6].
Txoj cai tsim nyog ntawm redox, mitochondrial dynamics, thiab mitophagy tau pom tias tseem ceeb hauv CKD [92, 93]. Txawm li cas los xij, txawm hais tias kev tiv thaiv los ntawm mitochondrial biogenesis tau raug txheeb xyuas, nws kuj tau pom tias muaj feem cuam tshuam nrog ntau dua fibrosis hauv DKD [7]. Tsis tas li ntawd, cov txiaj ntsig proangiogenic tshwm sim nyob rau hauv lub sijhawm ntev yog suav tias ua rau muaj kev cuam tshuam ntawm hypoxia hauv lub raum hauv cov hlwb [68]. Nws yuav tsum raug sau tseg tias kev ua kom Nrf2 thaum ntxov tau pom tias muaj kev tiv thaiv los ntawm ntau yam qauv ntawm AKI thiab CKD uas muaj feem cuam tshuam nrog kev txhim kho hauv mitochondrial homeostasis, thiab kev ua kom lig ntawm Nrf2 tau pom tias muaj feem cuam tshuam nrog kev cuam tshuam loj heev hauv Cov kev sim tshuaj tau ua rau cov neeg mob uas muaj CKD lig (Daim duab 3).
Raws li lub hauv paus uas mitochondrial homeostasis hloov mus rau lub xeev tus kab mob, thiab cov pov thawj uas tau sau los ntawm ntau cov kev tshawb fawb, peb xav hais tias Nrf2, uas tswj cov mitochondrial homeostasis, tej zaum yuav muaj zog tiv thaiv nyob rau hauv AKI tshaj li nyob rau hauv CKD. Yog li, Nrf2 ua kom muaj peev xwm kho tau hauv cov kab mob raum, thiab tshwj xeeb tshaj yog hauv AKI, tab sis qhov no yuav tsum tau soj ntsuam hauv kev sim tshuaj ntxiv. Ntxiv mus, cov txheej txheem ntawm cov kev tsis zoo tshwm sim rau Nrf2 activator nyob rau hauv cov neeg mob nrog CKD yuav tsum tau qhia meej, txhawm rau coj nws txoj kev siv tshuaj kho mob. Interestingly, Nrf2 activators, flavonoids, tau pom muaj ob qho kev cuam tshuam hauv kev kho mob qog noj ntshav, tej zaum yog vim qhov tsis ua haujlwm ntawm kev tswj hwm kom ncav cuag cov txiaj ntsig inhibitory concentration, uas muab cov tswv yim muaj txiaj ntsig rau Nrf2 activators ua rau toxicity [98].
Cov ntaub ntawv
[1] AS Levey thiab MT James, "Acute raum raug mob," Annals of Internal Medicine, vol. 167, Nr. 9 Ib., 66–80, 2017.
[2] AC Webster, EV Nagler, RL Morton, and P. Masson, "Nyob raum Kab Mob," Lancet, vol. 389, Nr. 10075, pp. 1238–1252, 2017
[3] N. Nourbakhsh thiab P. Singh, "Lub luag haujlwm ntawm lub raum oxygenation thiab mitochondrial muaj nuj nqi hauv pathophysiology ntawm mob raum.
[4] AS Gonzalez, ME Elguero, P. Finocchietto li al., "Qhov txawv txav mitochondrial fusion-fission tshuav nyiaj li cas pab txhawb rau kev nce qib ntawm kev sim sepsis," Free Radical Research, vol. 48, Nr. 7, nr 769–783, 2014.
[5] KA Rasbach thiab RG Schnellmann, "PGC-1 overexpression txhawb kev rov qab los ntawm mitochondrial dysfunction thiab cell raug mob," Biochemical thiab Biophysical Research Communications, vol. 355, Nr. 3 Ib., 734–739, 2007.
[6] M. Jiang, M. Bai, J. Lei et al., "Mitochondrial dysfunction and the AKI-to-CKD transition," American Journal of PhysiologyRenal Physiology, vol. 319, Nr. 6, p. F1105–f1116, 2020.
[7] SY Li, J. Park, C. Qiu et al., "Kev nce qib ntawm peroxisome proliferator-activated receptor coactivator-1 hauv podocytes ua rau muaj kev cuam tshuam ntawm glomerulopathy," JCI Kev pom, vol. 2, nre. Peb Hlis 14, 2017.
[8] H. Motohashi thiab M. Yamamoto, "Nrf2-Keap1 txhais cov txheej txheem kev ntxhov siab tseem ceeb ntawm lub cev," Trends in Molecular Medicine, vol. 10, nr. 11, pp. 549–557, 2004.
[9] MP Chin, D. Wrolstad, GL Bakris li al., "Risk yam tseem ceeb rau lub plawv tsis ua hauj lwm nyob rau hauv cov neeg mob uas muaj hom 2 mob ntshav qab zib mellitus thiab theem 4 mob raum kab mob kho nrog bardoxolone methyl," Journal of Cardiac Failure, vol. 20, nr. 12, pp. 953–958, 2014.
[10] D. Nolfi-Donegan, A. Braganza, thiab S. Shiva, "Mitochondrial electron thauj saw: oxidative phosphorylation, oxidant ntau lawm, thiab txoj kev ntsuas," Redox biology, vol. 37, xov 101674, 2020.
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