Pyroptosis: A New Frontier in Kidney Diseases Part 2

4.4. Kab mob raum Inflammatory. Lupus nephritis (LN) yog ib qho teeb meem ntawm cov kab mob lupus erythematosus (SLE). Clinically, kwv yees li 50 feem pua ​​​​ntawm cov neeg mob yuav muaj teeb meem LN. Lub pathogenesis ntawm LN yog feem ntau muaj feem xyuam rau inflammatory cell infiltration, ua kom cov ntshav coagulation yam, thiab tso tawm inflammatory mediators tshwm sim los ntawm lub deposition ntawm lub cev tsis muaj zog complexes nyob rau hauv lub glomeruli. Cov neeg mob uas muaj kab mob raum interstitial thiab kab mob vascular feem ntau muaj kev raug mob rau lub raum hnyav dua thiab muaj qhov tsis zoo.

Yav tas los, inflammatorymediator IL-18 yogxav tias ua lub luag haujlwm tseem ceeb hauv LN. NLRP3-ASC-caspase-1 txoj kev taw qhia tau ua ib feem tseem ceebnyob rau hauv lub raum raug mob ntawm SLE [79, 80]. Lub luag haujlwm ntawm P2X7 hauvTxoj kev uas tsis yog-canonical pyroptosis tau raug pov thawj tias yogmuaj feem xyuam rau kev ua kom cov caspase-1. Xyoo 2013, Zhaoua al. [81] pom tias inhibition ntawm P2X7/NLRP3/caspase-1 taw qhia txoj kev zootxhim kho LN. ACov kev tshawb fawb ntxaws tau ua hauv 2017 tau lees paubuas inflammatorylub cev NLRP3 tau qhib rau cov neeg mob thiabnas nrog LN, ua rau Sertoli cell raug mob thiab hnyav heevalbuminuria [82]. Cov txiaj ntsig no qhia qhov tseem ceebntawmNLRP3 inflammatorycev v LN. Piperine tau pomtxhawm rau txo LN los ntawm inhibiting SLE nas qauv thiabtib neeg ze-kawg lub raum tubular epithelial cell pyroptosis,qhia txog lub luag haujlwm ntawm pyroptosis hauv kev loj hloblos ntawm LN [83]. Thaum lub sij hawm tshwm sim thiab kev loj hlob ntawm LN,kev sib raug zoo ntawm NLRP3 thiab pyroptosis tsis yogmeej. Seb NLRP3 cleaves SGDMD, ib qho tshwj xeebsubCov tswv yim rau pyroptosis, tseem yuav tau kawm.

IgA nephropathy (IgAN) yog feem ntau pom primary glomerular kab mob, uas txhais tau hais tias feem ntau yog IgA lossis IgAdeposition ntawm mesangial cheeb tsam ntawm glomeruli, thiab yognrog los ntawm kev muaj lossis tsis muaj lwm yam IgAs. Nws yogkwv yees tias 20 feem pua–40 feem pua ​​​​ntawm cov neeg mob nrog IgAN yuav txhim khokab mob raum kawg hauv 20 xyoo [84]. Yog li ntawd, ibtshawb nrhiav rau hauv cov kab mob pathogenesis thiab cov yam tseem ceebntawm IgA raum kab mob tuaj yeem muab cov ntaub ntawv tseem ceebrau kev kho mob.

Ib txoj kev tshawb fawb tau ua nyob rau hauv 1997 qhia txog kev koom tes ntawmcov inflammatorynruab nrab IL-1 nyob rau hauv qhov kev loj hlob ntawmIgAN, qhia txog lub luag haujlwm tseem ceeb ntawm kev mobhauvIb [85]. Tsis ntev los no tau tshaj tawm tias qhov kev qhiantawm NLRP3 yog qhov tseem ceebnce nyob rau hauv lub raum tubulesntawm cov neeg mob nrog IgAN [86, 87].

4.5. Lwm yam.Tam sim no, qhov tshwm sim thiab kev vam meej ntawmntau yam kab mob raum muaj feem xyuam nrog pyroptosis. Txawm li cas los xij,vim nws tsis tau kawm zoo, qhov no tsis tau lees paub. Calcium oxalate (CaOx) nephropathy yog tshwm sim los ntawm covntau dhau ntawm CaOx nyob rau hauv lub raum, thaum kawgua rau mob raum kawg. Nws pom tiasCaOx crystals tuaj yeem pib IL-1 - nyob rau hauv innatekev tiv thaiv los ntawm kev ua kom NLRP3/ASC/caspase-1 signalingtxoj kev ntawm lub raum mononuclear phagocytes, ua raunas raum tubular raug mob thiab txhawb txoj kev loj hlobntawm CaOx nephropathy [88, 89]. Ib yam li ntawd, NLRP3 accelerated glomerular sclerosis hauv CaOx nephropathy nasqauv thiab coj mus rau lub raum ua haujlwm tsis zoo los ntawmmediating ib inflammatorycov lus teb [90]. Meanwhile, lubntev-coding RNA LINC00339 tau raug pov thawj los ua kom lub raumtubular epithelial cell pyroptosis hauv cov neeg mob uas muaj CaOxnephropathy los ntawm kev ua kom NLRP3 ntawm miR-22-3p [91].Ntau yam teeb meem tuaj yeem tshwm sim nyob rau theem pib ua rawsnyob rau hauv lub raum transplantation. Ntxiv mus, nws tau qhia tiasKev hloov lub raum tuaj yeem ua rau lub raum mob thiab nyob deb kawg ntawm lub siab raug mob hauv nas. Cov cim ntsig txogpyroptosis nce markedly, tab sis kev sib raug zoo ntawmteeb meem tshwm sim los ntawm lub raum transplantation thiabpyroptosis xav tau kev tshawb nrhiav ntxiv [92]. Lub pathophysiologicalcov txheej txheem ntawm HIV thiab HIV cuam tshuam rau lub raumkab mob thiab mob raum ua rau raug mob los kuj yogze ze rau pyroptosis [93, 94]. Cov nokev tshawb pommuajmuab ib tug theoretical rational rau qhov nrhiav tau ntawm kev kho tshiabcov hom phiaj thiab cov kev hloov kho physiopathological hauvntau yam kab mob raum.

5. Cov tshuaj muaj peev xwm rau Pyroptosis hauvKab mob raum

Nyob rau hauv cov kev tshawb fawb txog pyroptosis nyob rau hauvtebntawm me nyuamney kab mob, ob peb tau tsom rau cov proteins uas muaj feem xyuam rau covpyroptosis signaling pathway, uas yog, NLRP3, caspase-1,thiab tus inhibitor lossis activator ntawm GSDMD (Table 2). Quercetin, curcumin, thiab allopurinol tau pom tag nrho los tiv thaiv hyperuricemiathiab antihyperlipidemic muaj nuj nqi thiab txotso tawm inflammatoryyam los ntawm inhibiting lub activainflammatory txheej txheemlub cev NLRP3 hauv lub raum hlwb, yog li ntawdncua kev nce qib ntawm DKD [95, 96]. Nws kuj pomuas CP-456,773, ib qho tshwj xeebinhibitor ntawm NLRP3, tuaj yeem ncua sijhawmkev loj hlob ntawm nas raumfibrosisvim nws qhov ntxov ntxovinhibitory nyhuv[97]. Ib txoj kev tshawb fawb tsis ntev los no qhia tias artemisinin, ib qho anti-inflammatorytshuaj, yuav alleviate naslub raum tubule interstitialfibrosisby downregulating NLRP3[98]. Peb reagents tsom inflammatorykab mob raumtau pom tias ncaj qha inhibit qhov ua kom NLRP3.Epigallocatechin-3-gallate (EGCG) thiab Bay{1}} tuaj yeemFeem ntau txo cov kev hloov pauv pathological ntawm lupus nephropakoj, icariin, aflfl uaavonoid los ntawm Suav tshuaj ntsuab,Herba epimedium, ua tau zooresists cov inflammatorytshuaj tiv thaivhauv nas nrog IgAN [99–101] ib. Tsis tas li ntawd, qee cov tshuajindirectly inhibit qhov ua kom NLRP3. Mdivi-1,dynamics-related protein 1 (DRP1), txo cov tsos mobntawm AKI nas los ntawm kev tiv thaiv mitochondrial muaj nuj nqi thiab inhitom qhov ua kom NLRP3 [102]. Tsis tas li ntawd, piperine tseem ceeb heevinhibited qhov ua kom NLRP3 inflammatorylub cev thiab txo qhov tso tawm ntawm proinflammatorycytok uaines thiab nas lub raum tubule pyroptosis los ntawm lub hom phiajAMPK los tiv thaiv kev txhim kho ntawm LN [83]. Zhen-wutang yog ib lub npe nrov suav tshuaj ntsuab tshuaj ntsuab uasinhibits kev ua haujlwm ntawm NLRP3 thiab ncua kev txo qisntawm lub raum ua haujlwm hauv IgAN nas los ntawm kev txhim kho qhov zais ciaLub raum exosomes [103]

Caspase-1 yog qhov txuas tseem ceeb hauv txoj kev pyroptosis; uasyog, tus inhibitor ntawm caspase-1 kuj inhibits qhov tshwm sim thiabKev loj hlob ntawm pyroptosis. Cov txiaj ntsig tau pom tias kev txo qisntawm -hydroxybutyrate thiab kev qhia ntawm proinflammatorycytokines tuaj yeem txo cov kab mob pathological hauv AKInas los ntawm inhibiting pyroptosis [104]. Mizoribine tuaj yeem ua tauinhibit qhov inflammatorytshuaj tiv thaiv nyob rau hauv lub raum ntawm lub raumfibrosisnas los ntawm inhibiting caspase -1 thiab alleviating cov tsos mobntshav siab [105]

Raws li qhov tshwj xeebsubstrate ntawm pyroptosis, GSDMD yog qhov tseem ceeblub hom phiaj rau kev tswj ntawm lub raum pyroptosis. Nws pomtias sodium butyrate alleviated pyroptosis ntawm glomerular vascular endothelial hlwb hauv DKD nas, muab ibLub hom phiaj tshiab rau kev kho mob ntawm DKD [69]. Kev tshawb fawb tsis ntev los notshaj tawm tias Catalpol thiab Geniposide tuaj yeem txo qhov kev pheej hmooCov tsos mob ntawm DKD nas los ntawm inhibiting pyroptosis ntsig txogcov proteins, xws li GSDMD thiab GSDMD-N. Tau kawg,muaj ntau yam tshuaj rau cov kab mob raumlos ntawm kev tiv thaiv pyroptosis [107, 108]. Riboflavinraug txiav txim siabib qho anti-inflammatoryvitamin vim nws cov antioxidantkev ua si. Riboflfl uaavin tau pom kom ncua pyroptosis thiab covtso tawm IL-1 thiab IL-18 los ntawm inhibiting kev ua komAIM2 thiab lwm yam kab mob. Tam sim no, kev tshawb fawb txogAIM2 inhibitors thiab pyroptosis yog txwv raumob qog noj ntshav. Seb AIM2 inhibitors tuaj yeem ua haujlwm los ntawm inhibitingpyroptosis xav tau kev tshawb nrhiav ntxiv. Yog li, ntxivkev tshawb fawb ntawm lub ncauj lus tau txhawb siab heev [108]. Zuag qhia tag nrho,cov kev tshawb fawb tam sim no muaj lawv tus kheej txwv thiab xav taukev lees paub ntxiv.

6. Kev Pom Zoo thiab Cov Ntsiab Lus

Hauv cov ntsiab lus, pyroptosis feem ntau yog tswj hwm los ntawm caspase -1- amediated canonical pathway thiab lub caspase-4/5/11-mediated noncanonical txoj kev. Qhov tshwm sim thiab kev vam meejCov kab mob raum muaj ntau dua los yog tsawg dua cuam tshuam nrog pyroptosis, thiabcov inflammatorylub cev NLRP3 yog qhov kev kawm zoo tshaj plaws. Qhov notshuaj ntsuam xyuas qhov tseem ceebpyroptosis nyob rau hauv lub pathogenesisntawm mob raum raug mob, mob ntshav qab zib raum, raumfibrosis, thiab inflammatorykab mob raum. Lub luag haujlwm ntawm pyroptosis li aLub hom phiaj tseem ceeb rau kev kho mob raum kab mob kuj yogtseem ceeb. Txawm li cas los xij, muaj ntau yam teeb meem tseem nyobhais nyob rau hauv lub cev ntawm kev tshawb fawb.

Tam sim no, txoj kev tshawb fawb ntawm pyroptosis tseem nyob hauv nws cov me nyuam mos;muaj ntau cov lus nug tsis teb. Piv txwv li,Txawm hais tias caspase protein tsev neeg plays lub luag haujlwm tseem ceeb hauvpyroptosis, tsis hais tus canonical thiab noncanonicaltxoj kev, lawv kuj yog cov proteins tseem ceeb regulating nruab nrabthiab theem kawg ntawm apoptosis. Muaj, thaum twg yog kev sib raug zoontawm pyroptosis thiab apoptosis? Puas yog pyroptosis ywj siabhom kev tuag ntawm tes, los yog nws nrog rau lwm homntawm cell tuag? Hauvflammation yog tus txheej txheem tseem ceeb ntawm kev kho kom haum xeeb pyroptosis, thiab oxidative kev nyuaj siab yog ib qho uas nquag pom nyob rau hauv inflammatorycov tshuaj tiv thaiv. Muaj peev xwm oxidative kev nyuaj siab ncaj qha kho kom haumpyroptosis? Cov kev tshawb fawb ntawm pyroptosis tau muaj ntau ntauntawm ob lub cim cim, GSDMD thiab GSDME. Ntau qhov kev tshawb fawbtau nyiam nthuav tawm NT terminals ntawm ob tus proteins thiab tshawb xyuas oligomer-triggered pyroptosis.Txawm li cas los xij, tsis muaj ib qho kev tshawb fawb tau tshaj tawm dawb NT davhlau ya nyob twg-kho khopyroptosis. Cov lus nug zoo li no tseem yuav tsum tau ua pov thawjlos ntawm ntau txoj kev tshawb fawb.

Pyroptosis tiag tiag yog ob-edged ntaj. Thaum twg pyoptosis tshwm sim nyob rau hauv ib txwm hlwb ntawm lub raum cov ntaub so ntswg, uas yog, Sertolicov hlwb thiab lub raum tubular epithelial hlwb, ntau lub raum ntsig txogkab mob yuav tshwm sim. Feem ntau ntawm kev tshawb fawb txog pyroptosisthiab kab mob raum tau tsom rau qhov no. Lub caij no,nruab nrab pyroptosis yog ib qho tseem ceeb tiv thaiv kab moblub cev uas ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mobthiab endogenous txaus ntshai yam. Piv txwv li, yuav tshem tawm ntawmraug mob hlwb los yogfibroblastsnyob rau hauv lub raum cov ntaub so ntswg los ntawm pyroptosis alleviate the degree ntawm cov kab mob raum? Ob peb txoj kev kawmpuas tau hais txog qhov teeb meem no. Yog li ntawd, kev kawm ntxiv yogxav kom paub meejqhov kev xav no.

Tam sim no, ntau cov tshuaj tau pom tias ua haujlwmlos ntawm kev tswj cov kab mob pyroptosis. Txawm li cas los xij, kev tshawb fawb muajfeem ntau tsom rau ntawmtebntawm kev kho mob qog noj ntshav. Kev tshawb fawbthiab kev loj hlob ntawm cov tshuaj rau kev kho mob ntawm lub raum ntsig txogkab mob tsis tu ncua. Yav tom ntej, cov tshuaj tartau txais pyroptosis rau kev kho mob ntawm lwm yam kab mob tuaj yeem ua taukuaj mob raum kab mob, thiab cov tshuaj tshiab raukev kho mob raum kab mob tuaj yeem tsim losphiaj pyroptosis. Qhov no yuav muab kev taw qhia zoo duarau kev txhim kho cov tshuaj rau lub raum ntsig txogkab mob.

Cov ntawv luv

AIM2: Tsis muaj melanoma 2

AKI: Mob raum raug mob

AMPK:Adenosine 5′Monophosphate (AMP-)activated protein kinase

ASC: Apoptosis-associated speck-zoo li proteinmuaj CARD

ATP: Adenosine triphosphate

box: Zincntiv tessau npe

CaOx: Calcium oxalate

CARD: Caspase activation thiab recruitment domain

CC:Ib co coiled-coil domain

CHOP: C/EBP homologous protein

CKD: Mob raum mob

DAMPs: Kev puas tsuaj cuam tshuam nrog cov qauv molecular

DN:Mob ntshav qab zib nephropathy

DNA: Deoxyribonucleic acid

DRP1: Dynamics-related protein 1

EGCG: Epigallocatechin-3-gallate

ESRD: End-stage renal disease

GSDMD: Gasdermin D

GSDME: Gasdermin E

HIV: Human immunodeficiencykab mob vais lav

HMGB1: High-mobility group box 1 protein

IgAN: IgA nephropathy

IB -1 : Interleukin -1  

IL -18: Interleukin -18

IRI:Ischemia-reperfusion raug mob

LN:Lupus nephritis

lncRNAs: Ntev noncoding

RNAsLPS:Lipopolysaccharide

LRRs: Leucine-nplua nuj rov ua dua

LT:Anthrax tua kab mob

MALAT1: Metastasis-associated ntsws adenocarcinomantawv sau 1

miR: MicroRNA

MLKL: Mixed lineage kinase domain-like protein

NAIP: NLR tsev neeg, apoptosis inhibitory protein

NCCD: Nomenclature Committee on Cell Death

NEAT1: lncRNA-Neat 1