Abstract

Cov nroj tsuag-derived toxin aristolochic acid (AA) yog qhov ua rau herbal nephropathy thiab Balkan nephropathy. Kev noj tshuaj AA siab tuaj yeem ua rau mob raum raug mob, thaum noj cov tshuaj AA tsawg tuaj yeem ua rau mob raum tsis zoo. Noj AA yog coj los ntawm lub raum tubular epithelial hlwb, ua rau DNA puas thiab cell tuag. Procyclin D (CypD) muaj feem xyuam rau mitochondria-nyob ntawm tes tuag, tab sis seb qhov txheej txheem no ua lub luag haujlwm hauv qhov mob hnyav lossis mob raum mob AA yog tsis paub meej. Peb tau hais lo lus nug no los ntawm kev nthuav tawm CypD-/- thiab cov tsiaj qus (WT) nas kom mob siab lossis mob AA. 5 mg / kg AA gavage rau 3 d hauv WT nas ua rau mob raum raug mob raws li pov thawj los ntawm kev poob ntawm lub raum ua haujlwm, tubular cell raug mob thiab tuag, thiab neutrophil infiltration. Tag nrho cov kev ntsuas no tau txo qis hauv CypD-/- nas. Kev noj tshuaj tsawg tsawg (2 mg / kg AA) kev tswj hwm hauv WT nas ua rau mob raum mob nrog rau lub raum tsis ua haujlwm thiab lub raum fibrosis los ntawm 28 hnub. Txawm li cas los xij, CypD-/- nas tsis tiv thaiv AA-induced mob raum kab mob. Hauv kev xaus, CypD txhawb nqa AA-vim lub raum raug mob, tab sis CypD tsis txhawb kev hloov pauv ntawm lub raum raug mob mus rau mob raum mob thaum lub sijhawm raug AA.

Ntsiab lus

mob raum mob; aristolochic acid; cell tuag; mob raum mob; cyclophilin D; mob; raum fibrosis;Cistanche tubulosa

Nyem qhov no mus yuavCistanche extract

Taw qhia

Aristolochic acid (AA) yog ib tug nitro phenanthrene carboxylic acid nyob rau hauv tsev neeg Aristolochiaceae, uas muaj ze li ntawm 500 hom nroj tsuag.AA muaj feem ntau yog sib tov ntawm ob metabolites, 8-methoxy-6-necrophilic-(3 ,4-d)-1,3-deoxy-5-carboxylic acid (AAI) thiab 6-necrophilic-(3,4-d){{ 13}}, 3-deoxy-5-carboxylic acid (AAII) [1]. Kev soj ntsuam ntawm cov kab mob raum endemic nyob rau hauv Balkans tau txheeb xyuas AA raws li nephrotoxin lub luag haujlwm rau tus kab mob no ib puag ncig [2]. Aristolochia hom loj hlob nyob rau hauv thaj chaw ntawm cov qoob loo hauv cheeb tsam muaj paug cov hmoov ci, thiab kev noj AA ntev ntev ua rau mob raum, pob zeb raum, thiab mob qog noj ntshav [1]. Aristolochia spp. kuj tseem siv rau hauv kev npaj ntawm ntau yam tshuaj ntsuab tshuaj ntsuab uas AA tau raug txheeb xyuas tias yog cov tshuaj lom hauv tshuaj ntsuab nephropathy [3]. Hauv kev tshawb fawb ntawm 300 cov neeg mob uas muaj tshuaj ntsuab nephropathy, mob raum raug mob thiab mob raum qeeb qeeb tau cuam tshuam nrog qib siab lossis qis qis ntawm AA, raws li [4]. Kev txheeb xyuas ntawm AA raws li cov tshuaj lom hauv cov kab mob no ua rau lub sij hawm aristolochic acid nephropathy (AAN). Tsis muaj kev kho mob rau AAN, yog li nws yog ib qho tseem ceeb kom nkag siab txog cov txheej txheem uas AA ua rau mob raum mob thiab mob ntev.

Lub raum tubular epithelial hlwb yog rhiab heev rau AA toxicity vim hais tias lawv qhia cov organic anion transporter protein OAT1/3, uas yog muaj peev xwm mus nqa AA mus rau hauv lub hlwb [5]. Intracellularly, AA reacts nrog DNA bases los tsim DNA adducts uas yuav ua tau rau ib tug: T → T: ib tug transformation, ua rau DNA puas thiab tej zaum yuav mob cancer [1]. Tsis tas li ntawd, AA induces kev tuag ntawm kab lis kev cai tubular epithelial hlwb los ntawm inducing qib siab ntawm reactive oxygen hom (ROS) [6]. Ob leeg nas thiab nas yog rhiab heev rau cov tshuaj lom ntawm AA thiab yog li cov txheej txheem ntawm AA-induced nephrotoxicity tuaj yeem tshawb xyuas hauv vivo. Ib koob tshuaj ntau tshaj ntawm AA-induced mob raum tsis ua haujlwm nrog tubular necrosis hauv cov tsiaj, qhov rov ua dua qis dua ntawm AA-induced mob raum mob nrog tubular atrophy thiab fibrosis [7,8].

Procyclins yog ib pawg ntawm cov enzymes uas nthuav dav nrog peptidyl cis-trans isomerase (PPIase) kev ua haujlwm uas koom nrog hauv cov protein folding. Cyclophilin D (CypD), tseem hu ua Peptidylprolyl Isomerase F (PPIF), yog ib feem ntawm mitochondrial membrane permeability transition pore (mPTP). Tom qab kev raug mob ntawm tes, mPTP yog qhib vim ROS ntau dhau los yog lwm yam kev ntxhov siab, ua rau kev tso tawm ntawm cytochrome c mus rau hauv cytoplasm thiab tom qab cell tuag [9]. CypD gene deletion nas yog phenotypically, tab sis CypD-/- nas yog resistant rau lub raum ischemia/reperfusion raug mob los yog cisplatin toxicity-induced tubular necrosis thiab mob raum tsis ua hauj lwm [10-13]. Tsis tas li ntawd, CypD-/- nas muaj kev tiv thaiv ntawm unilateral ureteral obstruction (UUO) qauv ntawm lub raum fibrosis [14]. Txawm li cas los xij, nws tsis paub meej tias CypD ua lub luag haujlwm hauv AA-induced TEC raug mob. Hauv txoj kev tshawb fawb tam sim no, peb tau tshawb xyuas lub luag haujlwm ntawm CypD nyob rau hauv high-dose AA-induced mob raum raug mob thiab ntev-dose AA-induced raum fibrosis.

Herbal Cistanche

Cov txiaj ntsig

Cyclophilin D Deletion tiv thaiv Aristolochic Acid-Induced Acute raum Injury

Plasma creatinine qib hauv cov tsiaj qus zoo (WT) C57BL6 / J nas nyob ntawm 8 txog 16 μ mol / L. Kev tswj hwm ntawm 5 mg / kg AA rau WT nas ua rau lub raum ua haujlwm tsis zoo rau hnub 3, txhais tau tias yog 3-plasma creatinine ntau ntxiv (ntau txog 30 txog 53 μ mol / L). Piv nrog WT cov nas tswj, tubular epithelial hlwb ntawm WT nas tau ua rau muaj kev puas tsuaj rau hnub 3 tom qab AA cov thawj coj. Lub apical txhuam ciam teb tau ploj lawm, hlwb tau o, nuclei ploj, hlwb raug tso rau hauv tubular lumen, thiab casts tau tsim nyob rau hauv tubular lumen. Tubular necrosis tau pom nyob rau hauv siab magnification. Peb kuj tau soj ntsuam cov cell tuag los ntawm staining rau cleaved caspase 3. WT tswj nas tsis muaj cleaved caspase 3 stainings, tab sis nyob rau hnub 3 tom qab AA tswj, ib tug loj tus naj npawb ntawm tubular epithelial hlwb pom cleaved caspase 3 stainings. Raws li cov histological nta ntawm cell raug mob thiab cell tuag, mRNA theem ntawm tubular raug mob marker Kim1 tau nce siab, whereas mRNA qib ntawm cov protein tiv thaiv -Klotho tau txo qis.

Lub raum qauv thiab kev ua haujlwm tau zoo li qub hauv CypD gene deletion (CypD-/-) nas. Ib qho kev tswj hwm ntawm 5 mg / kg AA tau tiv thaiv CypD-/- nas los ntawm mob raum mob. Txawm hais tias plasma creatinine qib tau nce siab me ntsis hauv 5/10 CypD-/- nas, txhais tau tias cov ntshav creatinine qib qis dua hauv WT AA pawg thiab tsis txawv ntawm cov CypD-/- tsis kho nrog AA. Ib daim duab zoo sib xws tau tshwm sim hauv kev soj ntsuam ntawm lub raum tubular raug mob, nrog rau CypD-/- hnub 3 AA pawg qhia txog kev txo qis hauv histological tubular raug mob, cleaved caspase-3- cov xov tooj ntawm tes, thiab Kim1 mRNA qib, nrog rau ib qho tseem ceeb tiv thaiv kev txo qis -Klotho mRNA qib.

Cyclophilin D Deletion tiv thaiv Acute Aristolochic Acid-Induced Leukocyte Infiltration

Neutrophils tsis tshua muaj nyob hauv ob lub raum ntawm WT thiab CypD-/- tswj pawg. Txawm li cas los xij, ntau tus Ly6G ntxiv rau neutrophil infiltrates tau tshwm sim hauv thaj tsam ntawm tubular raug mob hauv WT nas nyob rau hnub 3 tom qab AA tswj hwm. neutrophil infiltration tau txo qis hauv CypD-/- ib pawg. Hauv kev sib piv rau cov neutrophils, muaj coob tus neeg nyob hauv F4/80 ntxiv rau macrophages hauv WT thiab CypD-/- tswj lub raum. Txawm hais tias macrophages tau nce hauv thaj tsam ntawm tubular raug mob, lawv tsis ncav cuag qhov tseem ceeb hauv pawg WT AA lossis CypD-/- AA pawg. t hlwb tsis tshua muaj nyob hauv WT thiab CypD-/- tswj lub raum. Ib qho me me tab sis tseem ceeb T-cell infiltrate tau pom nyob rau hauv ob lub raum ntawm WT thiab CypD-A nas nyob rau hnub 3 AA, txawm hais tias tsis muaj qhov sib txawv ntawm WT thiab CypD-/- nas.

Cyclophilin D Deletion Tsis Tiv Thaiv Kab Mob Aristolochic Acid-Induced raum Kab Mob

WT nas muab 2 mg/kg AA txhua 2 hnub rau 28 hnub ua rau muaj kab mob raum ntev nrog 2.6-plasma creatinine ntau dua. Kev kuaj mob histological qhia pom qhov tseem ceeb ntawm tubular atrophy thiab dilatation, ib nrab tubular casting tsim, thiab qhov tseem ceeb ntawm glomeruli. hnub 28 AA ntawm WT tsis pom qhov tseem ceeb ntawm tubular necrosis, tab sis muaj qhov tseem ceeb lysis ntawm ntau cov caspase 3-stained cells (tej zaum apoptotic cells), txawm hais tias qhov no tau txo los ntawm 66 feem pua ​​​​piv rau hnub 3 ntawm WT AA. (P < 0 001). Kim1 mRNA qib nce thiab a-Klotho mRNA qib txo qis hauv WT AA pab pawg hnub 28; Cov kev hloov pauv no tau ntau dua hauv WT AA pab pawg hnub 3 (; p <0.001). CypD-/- nas tsis tiv thaiv kab mob AA-induced raum ntev. Lawv tau nthuav tawm cov qib plasma creatinine, kev puas tsuaj histological, Kiml thiab a-Klotho mRNA qib, thiab ntau cov cleaved caspase 3-stained cells piv rau cov hnub 28 AA WT nas.

Cyclophilin D Deletion Tsis Tiv Thaiv Kab Mob Aristolochic Acid-Induced Renal Fibrosis

Interstitial fibrosis yog ib qho cim ntawm cov kab mob raum ntev thiab yog tus cwj pwm los ntawm collagen deposition, aggregation ntawm -SMA ntxiv rau myofibroblasts, macrophage infiltration, thiab poob ntawm peritubular capillaries [15]. Piv rau WT thiab CypD-/- tswj lub raum, qhov twg hom IV collagen tau nyob rau hauv glomerular thiab tubular hauv qab daim nyias nyias (nrog rau phab ntsa hlab ntsha), diffuse type IV collagen deposition tau nce hauv thaj tsam interstitial ntawm 28- day AA WT nas. Ib 2-fold nce nyob rau hauv interstitial hom IV collagen deposition yog txuam nrog ib tug tseem ceeb nce nyob rau hauv lub raum hom I collagen mRNA theem. a 3. Hauv WT nas, kuj tseem muaj qhov tseem ceeb ntawm macrophage infiltration nyob rau hnub 28 AA, raws li muaj pov thawj los ntawm qib siab ntawm CD68 mRNA thiab nce siab ntawm CD206 - ib qho kev hloov pauv macrophage cim cuam tshuam nrog kev txhawb nqa lub raum fibrosis [15]. Tsis tas li ntawd, AA WT nas pom qhov tsis muaj CD31 ntxiv rau peritubular capillaries nyob rau hnub 28 piv rau WT tswj nas.

Herbal Cistanche

Kev sib tham

Tubular necrosis yog ib qho ntawm cov mob raum raug mob thaum muaj tshuaj lom, xws li tshuaj (xws li, cisplatin, vancomycin, gentamicin, thiab mucin) thiab Phytonephrotoxins (xws li, aristolochic acid thiab Cynarin) yog nyiam coj los ntawm lub raum tubular epithelial hlwb [16] . Ib qho tshwj xeeb ntawm cov kab mob coxin-induced tubular cell tuag yog mitochondrial puas. Piv txwv li, ntxiv rau qhov ua rau DNA puas tsuaj, mob raum raug mob los ntawm kev siv ntau ntawm cisplatin lossis aa yog ncaj qha cuam tshuam nrog kev puas tsuaj mitochondrial hauv lub raum tubular epithelial hlwb [17,18].

CypD plays lub luag haujlwm tseem ceeb hauv cov tshuaj lom mitochondria-dependent cell tuag los ntawm kev qhib mPTP [9]. Txoj kev tshawb fawb tam sim no pom tau tias yog thawj zaug uas CypD yuav tsum muaj nyob rau hauv high-dose aa-induced tubular epithelial cell tuag thiab mob raum raug mob. Qhov kev txiav txim siab no yog ua raws li CypD-/- cov nas uas ua rau lub raum ua haujlwm zoo dua qub, txo cov nqaij mos tubular raug mob thiab tubular cell tuag (raws li qhia los ntawm cleaved caspase 3 staining), txo qhov qhia txog tubular raug mob Kim-1, thiab a tiv thaiv kev poob ntawm a-Klotho qhia. Cov kev tshawb pom no zoo ib yam nrog cov kev tshawb fawb yav dhau los hauv vitro uas AA induces tubular epithelial cell tuag los ntawm induction ntawm mitochondria-derived reactive oxygen hom [19] thiab tias CypD yuav tsum tau rau reactive oxygen hom-induced cell tuag nyob rau hauv cultured tubular epithelial hlwb [14]. Tsis tas li ntawd, nyob rau hauv tus qauv AA mob, qhov sib xyaw ntawm neutrophils tau txo qis hauv CypD-/- nas. Me ntsis paub txog kev ua haujlwm ntawm CypD hauv neutrophils; Txawm li cas los xij, qhov txo qis hauv neutrophil infiltration tsuas yog qhov cuam tshuam ncaj qha ntawm qhov txo qis hauv tubular raug mob thiab tuag ntawm tes, uas txo qis ntawm kev pheej hmoo cuam tshuam txog cov qauv molecular ua rau txo qis neutrophil recruitment.10 Txawm hais tias neutrophils txhawb "nthwv dej thib ob" ntawm tubular. cell tuag nyob rau hauv cov qauv ntawm lub raum ischemia/reperfusion raug mob "[20-22], lub luag hauj lwm ntawm neutrophils lawv tus kheej nyob rau hauv mob AA-induced mob raum raug mob tsis tau txiav txim. 3 ntawm AA, tab sis tsis muaj qhov sib txawv ntawm WT thiab CypD-/- nas, tsis muaj qhov sib txawv ntawm cov raum macrophages hnub 3 ntawm AA qauv piv rau kev tswj hwm.

CypD-/- nas muaj kev tiv thaiv cov koob tshuaj AA-induced mob raum raug mob, uas zoo ib yam nrog cov kev tshawb fawb uas CypD-/- nas muaj kev tiv thaiv tubular epithelial cell tuag thiab poob ntawm lub raum ua haujlwm tom qab cisplatin lossis lub raum ischemia / reperfusion raug mob ( IRI) [10-12], thiab qhov kev kho mob nrog procyclidine inhibitors tiv thaiv IRI-induced mob raum mob [23].

Tau txiav txim siab tias CypD-/- nas muaj kev tiv thaiv los ntawm cov koob tshuaj AA-ua rau mob raum mob hnyav, peb xav tias cov nas no tseem yuav raug tiv thaiv los ntawm kev raug mob mus ntev rau cov tshuaj qis AA-induced tubular cell tuag thiab mob raum mob. Txawm li cas los xij, qhov no tsis yog qhov teeb meem, thiab CypD-/- nas tau nthuav tawm cov theem ntawm tubular cell raug mob (raws li Kim-1 thiab -Klotho), lub raum tsis ua haujlwm, thiab lub raum fibrosis tom qab kev tswj hwm qis AA uas tsis muaj. txawv ntawm WT nas.

Tej zaum yuav muaj ntau qhov laj thawj rau qhov tsis muaj kev tiv thaiv hauv CypD-/- nas thaum lub sij hawm tsis tshua muaj tshuaj AA. Kev soj ntsuam histological pom cov kab mob necrosis nyob rau hauv cov mob hnyav AA qauv, tab sis tsis yog nyob rau hauv tus qauv qis qis AA ntawm 28 hnub, thaum kev puas tsuaj tau tshwm sim hauv daim ntawv ntawm atrophy thiab apoptotic cell tuag (raws li qhia los ntawm lysis caspase 3 staining) . Qhov no qhia tias cov koob tshuaj AA siab ua rau tubular necrosis tab sis tsis yog koob tshuaj AA tsawg. Qhov no yuav yog vim qhov sib txawv ntawm cov pa oxygen reactive induction induced los ntawm qis thiab high-dose AA, los yog cov ciaj sia tubular hlwb yog resistant rau AA-induced necrosis. Cov kev tshawb fawb ntxaws ntxiv yog xav tau los cais cov txheej txheem ua tau los yog txheeb xyuas lwm qhov kev piav qhia, xws li tubular cell puas los ntawm kev puas tsuaj DNA hauv cov qauv AA ntev. Txawm li cas los xij, nws yog qhov tseeb tias CypD noob tshem tawm tsis tiv thaiv tubules los ntawm kev puas tsuaj rov qab los ntawm cov koob tshuaj qis ntawm AA. Tseeb tiag, qhov kev tshawb pom zoo sib xws tau pom nyob rau hauv cov qauv AA raug mob thiab mob ntev [24] siv JUN amino-terminal kinase (JNK) inhibitors. JNK thiab CypD tau koom nrog ROS-induced, mitochondria-dependent tubule cell tuag [14,24]. jNK inhibitor kev kho mob inhibits tubule cell tuag nyob rau hauv mob high-dose AA qauv, tab sis nyob rau hauv cov kab mob qis qis AA qauv [24] tsis muaj kev cuam tshuam rau tubular cell tuag lossis kev loj hlob ntawm lub raum fibrosis.

Cistanche ntxiv

Lub luag haujlwm tshwj xeeb ntawm CypD hauv lub raum fibrosis tau piav qhia hauv peb qhov kev tshawb fawb dhau los. Nyob rau hauv tus qauv unilateral ureteral obstruction (UUO), kev tswj hwm ntawm procyclidine inhibitors lossis kev siv CypD-/- nas tiv thaiv tubular cell tuag, myofibroblast tsub zuj zuj, collagen deposition, thiab peritubular capillary poob [14,23]. Txawm li cas los xij, kab lis kev cai WT thiab CypD-/- lub raum fibroblasts tsis txawv ntawm PDG-induced cell proliferation thiab TGF- 1-induced activation thiab collagen production [14], qhia tias CypD tsis ncaj qha cuam tshuam rau collagen-tsim myofibroblasts hauv txoj kev loj hlob. ntawm lub raum fibrosis. Yog li, hauv UUO qauv, kev tiv thaiv ntawm CypD-/- ntawm lub raum fibrosis nyob rau hauv nas yog vim qhov txo qis hauv tubular epithelial cell tuag thiab poob ntawm peritubular capillaries [14]. Hauv qhov sib piv, lwm txoj kev tshawb nrhiav pom tias CypD-/- nas pom muaj ntau dua glomerulosclerosis nyob rau hauv streptozotocin-induced type 1 diabetic nephropathy model, whereas kev kho mob nrog procyclidine inhibitor ua tsis tau tejyam los hloov txoj kev loj hlob ntawm glomerulosclerosis nyob rau hauv ib tug DB/DB qauv ntawm hom 2 diabetic. nephropathy [25]. Txoj kev tshawb fawb tam sim no pom tias CypD deficiency tsis muaj kev cuam tshuam rau kev loj hlob ntawm lub raum fibrosis nyob rau hauv tus qauv qis AA raug tus qauv, tsis muaj tubular epithelial cell tuag los yog peritubular capillary poob. Cov txiaj ntsig sib piv no hauv peb hom kab mob sib txawv qhia tias lub luag haujlwm ntawm CypD hauv kev loj hlob ntawm lub raum fibrosis yog nyob ntawm qhov xwm txheej ntawm lub raum raug mob thiab tej zaum yuav tsis yog qhov tseem ceeb rau lub raum fibrosis.

Cov lus xaus

Txoj kev tshawb fawb tam sim no tau lees paub qhov kev koom tes ntawm CypD hauv kev mob ntsws tubular necrosis thiab mob raum raug mob los ntawm kev siv tshuaj AA ntau. Hauv qhov sib piv, CypD tsis ua rau muaj kev phom sij ntawm cov kab mob AA uas tsis tshua muaj tshwm sim vim mob raum mob.

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Khai Gene Leong, Elyce Ozols, John Kanellis, Frank Y. Ma, thiab David J. Nikolic-Paterson