Rov nkag siab txog Glomerular Filtration Barrier Thiab Cov Kab Mob Muaj Feem Xyuam
Jan 12, 2023
Lub nephron yog lub hauv paus ntawm lub raum los ua nws txoj haujlwm, thiab glomerular filtration barrier yog ib txoj kab tseem ceeb ntawm kev tiv thaiv rau nws cov haujlwm physiological. Lub glomerular filtration barrier yog tsim los ntawm endothelial hlwb, podocytes, thiab glomerular qab daus daim nyias nyias (GBM), uas yog kev sib koom ua ke thiab koom tes ua kom tiav cov haujlwm ntawm glomerular filtration barrier. Muab qhov no, cov kab mob tshwm sim los ntawm kev puas tsuaj rau nws cov khoom siv tau dhau los ua ib qho tseem ceeb ntawm kev tshawb fawb kab mob hauv lub raum, xws li kab mob podocyte, kab mob GBM, hom IV cov kab mob ntsig txog collagen, thiab lwm yam.
Nyem rau cistanche deserticola extract rau raum mob
Nrog rau txoj kev loj hlob sai ntawm cov tshuaj genomic thiab kev txuas ntxiv txuas ntxiv ntawm cov kev tshawb fawb ntsig txog, tshwj xeeb tshaj yog cov kev tshawb nrhiav txuas ntxiv ntawm cov noob ntsig txog glomerular filtration barrier, peb txoj kev nkag siab txog kev tswj hwm kev tswj hwm ntawm glomerular filtration barrier thiab cov kab mob cuam tshuam kuj tau hloov kho tas li.
Thaum Lub Yim Hli 4, 2022, ntawm 2021 Academic Annual Meeting (CSN 2021) ntawm Nephrology ceg ntawm Tuam Tshoj Medical Association, kws kawm Liu Zhihong, tus thawj coj ntawm Eastern Theatre General Tsev Kho Mob thiab National Clinical Research Center for raum Disease, tau nthuav tawm ntawm "rov nkag siab txog glomerular Filtration Barriers thiab Cov Kab Mob Muaj feem xyuam". Academician Liu Zhihong tau taw qhia tias kev kawm cov kab mob uas sawv cev los ntawm Alport syndrome yuav tsum pib nrog kev tshuaj xyuas cov kab mob sib txawv ntawm cov noob, uas yuav muab peb txoj hauv kev tshiab kom nkag siab txog cov qauv txawv txav thiab kev cuam tshuam ntawm glomerular filtration barrier. Qhov nyuaj ntawm cov kab mob sib txawv ntawm cov noob caj noob ces, ntau hom kev kho mob phenotypes, thiab qhov tseem ceeb ntawm kev kuaj kab mob caj ces tau coj kev nkag siab tshiab, yog li txhim kho qib kev kuaj mob thiab kho cov kab mob zoo li no.
Gene variation thiab pathogenesis ntawm lub raum kab mob
Gene variation plays lub luag haujlwm tseem ceeb hauv qhov tshwm sim thiab kev loj hlob ntawm cov kab mob, suav nrog kev tswj hwm cov haujlwm ntawm cov noob / txoj hauv kev tseem ceeb thiab cov khoom siv ntawm tes ua haujlwm, thiab thaum kawg ua rau kev sib txawv thiab ua kom cov kab mob ntawm tes. Hauv kev kho mob, kab mob raum cuam tshuam nrog kev hloov pauv noob tsis yog qhov tsis tshua muaj. Kev kuaj pom tus nqi ntawm hom IV collagen gene mutations nyob rau hauv cov neeg mob uas muaj kab mob raum ntev (CKD) ua piv txwv: Tag nrho cov exome sequencing tau ua rau 3315 CKD cov neeg mob, thiab 307 (9.3 feem pua) cov neeg mob muaj pathogenic noob hloov, suav nrog 66 cov kab mob sib txawv. , suav nrog 27 tus neeg mob (9 feem pua) ntawm COL4A3, 21 tus neeg mob (7 feem pua) ntawm COL4A4, thiab 44 tus neeg mob (14 feem pua) ntawm COL4A5. Cov neeg mob Hematuria kuj tseem cuam tshuam nrog hom IV collagen noob hloov pauv. UK Biobank cov ntaub ntawv tsom xam pom tias COL4A4 p.Ser969 X yog qhov cuam tshuam loj tshaj plaws, ua raws li COL4A3 p.Gly695Arg thiab COL4A4 intron 25 Variant.
Hom IV collagen thiab laminin (laminin) yog ib qho tseem ceeb ntawm GBM, uas yog secreted los ntawm endothelial hlwb thiab podocytes thaum lub sij hawm kev loj hlob ntawm glomerular, thiab lawv cov noob hloov yuav ua rau cov proteins uas tsis ua rau ib txwm trimers, ua rau GBM mesh tus qauv poob thiab yooj yim hydrolyzed los ntawm proteolytic enzymes, uas tsis tsuas yog poob nws cov kev txhawb nqa, tab sis kuj ncaj qha cuam tshuam rau nws cov nyob ib sab podocytes thiab endothelial hlwb. Podocytes yog cov cell secretory tseem ceeb ntawm hom IV collagen thiab laminin, thiab lawv cov kev ua haujlwm tsis zoo yuav cuam tshuam rau kev tsim thiab kev ua haujlwm ntawm GBM. Piv txwv li, podocyte WT1 kev hloov pauv ua rau GBM diffuse thinning, nrog los ntawm kev hloov pauv thiab txheej txheej. INF2 kev hloov pauv ua rau GBM thinning thiab segmental delamination, fusion ntawm ko taw txheej txheem ntu, thiab lwm yam. Alport syndrome yog ib tus neeg sawv cev ntawm cov kab mob uas tau hais los saum toj no ua rau muaj kab mob.
Alport Syndrome
Peb qhov kev tshawb fawb ntawm Alport syndrome muaj keeb kwm ntev, uas tuaj yeem taug qab mus rau xyoo 1875. Txawm li cas los xij, tsis muaj cov lus qhia zoo sib xws rau kev kuaj mob thiab kev kho mob tuaj txog rau xyoo 2013.
01 Cov yam ntxwv ntawm caj ces thiab kev kuaj mob
Nyob rau theem pib ntawm kev loj hlob ntawm lub raum, 1 1 2(IV) thiab laminin-111 yog cov khoom tseem ceeb ntawm GBM. Raws li lawv paub tab, lawv maj mam hloov los ntawm 3 4 5(IV) thiab laminin -521, nws thiaj li tsim tau tus qauv GBM ruaj khov.
Vim hais tias cov txheej txheem saum toj no yog encoded los ntawm cov noob sib txawv, nws kuj ua rau muaj ntau haiv neeg ntawm cov qauv qub qub, xws li X-txuas Alport syndrome, autosomal recessive Alport syndrome, thiab autosomal dominant Alport syndrome. Ntawm lawv, cov txiv neej uas muaj X-txuas Alport syndrome yog mob hnyav thiab nquag tsim kab mob raum kawg (ESKD), thaum poj niam kuj mob me. Lub genotype ntawm autosomal recessive Alport syndrome yog homozygous lossis compound heterozygous kev hloov pauv, thiab qhov hnyav ntawm kev hloov pauv los ntawm hom kev hloov pauv zoo ib yam nrog X-txuas Alport syndrome. Autosomal dominant Alport syndrome muaj cov tsos mob me me.
Txij li qhov kev hloov pauv noob tau zoo sib xws rau qhov kawg ntawm kev kuaj mob, qhov nyuaj ntawm kev hloov pauv noob caj ces ntawm Alport syndrome yuav tsum raug lees paub hauv kev kho mob. Piv txwv li, seb tus neeg mob puas yog hom IV collagen gene mutation (hloov hom, hom kev hloov pauv), ob lub noob hloov, chimeric mutation, lossis polygenic mutation. Nrog rau kev txhim kho kev nkag mus tau ntawm cov cuab yeej tshuaj ntsuam genetic testing, kev kuaj caj ces ntawm Alport syndrome thiab cov neeg mob xav tias yuav tau pib tau txais kev saib xyuas ntawm cov kws kho mob. Txawm li cas los xij, vim tsis muaj kev cob qhia kev cob qhia thiab cov qauv thiab cov qauv tsim nyog, muaj qee qhov teeb meem hauv kev xa cov qauv, kev txhais cov txiaj ntsig, kev qhia txog caj ces, thiab kev tswj xyuas mus sij hawm ntev. Kev tshawb fawb ntxiv yog xav tau los tsim cov qauv thiab cov lus qhia rau kev ua haujlwm kho mob.
02 Pathogenic mechanism
Nyob rau theem pib ntawm kev loj hlob ntawm lub raum, 1 1 2(IV) thiab laminin-111 yog cov khoom tseem ceeb ntawm GBM. Raws li lawv paub tab, lawv maj mam hloov los ntawm 3 4 5(IV) thiab laminin -521, nws thiaj li tsim tau tus qauv GBM ruaj khov. Nyob rau hauv lub xeev pathological ntawm Alport syndrome, COL4A3-COL4A5 noob kev hloov pauv yuav cuam tshuam qhov kev nce qib ntawm cov txheej txheem kev hloov pauv no, 1 1 2(IV) thiab txawv txav laminin subtypes hloov qhov kev qhia ntawm matrix receptors thiab kev faib tawm ntawm cytoskeletal proteins, ua rau cov txheej txheem podocyte Foot txheej txheem fusion ploj mus thiab txhawb kev tso tawm ntawm matrix metalloproteinases (MMPs) hauv podocytes; Ntawm qhov tod tes, siab pom siab txhawb cov hlwb endothelial kom zais cov endothelin-1, uas tig mus ua kom cov hlwb mesangial thiab thaum kawg ua rau glomerular filtration barrier ua haujlwm txawv txav. Compensatory 1 1 2(IV) kev qhia tsis yog tsuas yog ua rau txo qis hauv GBM kev ruaj ntseg thiab yooj yim hydrolyzed los ntawm MMPs, tab sis kuj khi rau DDR1 thiab DDR2 receptors ntawm podocytes activates integrin-mediated inflammatory signaling pathways, thiab koom nyob rau hauv lub triggering thiab amplification ntawm lub zos o, induce activation ntawm RAAS system. Yog li ntawd, inhibiting RAAS activation, txo cov inflammatory teb nyob rau hauv lub zos, thiab anti-fibrosis yog suav hais tias yuav ua tau kev kho mob kom ncua kev loj hlob ntawm Alport syndrome.
03 Kev kho mob ntawm Alport syndrome
Tam sim no, kev kho mob ntawm Alport syndrome tuaj yeem muab faib ua plaub yam: ① RAAS inhibitors, xws li angiotensin-hloov enzyme inhibitors / angiotensin II receptor blockers (ACEI / ARB) lossis aldosterone receptor antagonists; ② inhibition ntawm inflammatory teb, xws li Nrf2 agonist, endothelin A receptor inhibitor; ③ anti-fibrosis, xws li Anti-miRNA-21; ④ Kev kho noob caj noob ces.
Retrospective cohort kev tshawb fawb thiab RCT cov kev tshawb fawb ntawm cov qauv tsiaj thiab cov neeg mob soj ntsuam tau lees paub tias ACEI / ARB tuaj yeem ncua qhov tshwm sim ntawm proteinuria hauv cov neeg mob Alport syndrome thiab ua kom lub raum ua haujlwm ntev, thiab tuaj yeem ncua sijhawm ESKD hauv cov neeg mob Alport syndrome. rau ntau tshaj kaum xyoo. Thiab cov nyhuv curative ntawm kev kho thaum ntxov yog qhov tseem ceeb dua. Cov txiaj ntsig ntawm peb qhov kev soj ntsuam tau pom tias cov lus teb rau ACEI / ARB kev kho mob hauv cov txiv neej cov neeg mob uas muaj X-txuas Alport syndrome tau cuam tshuam nrog genotype, thiab ACEI / ARB txoj kev kho tau ncua kev nce mus rau ESKD hauv cov neeg mob uas tsis muaj kev hloov pauv los ntawm 16 xyoo ( los ntawm 24 xyoo mus rau 40 xyoo). xyoo), ncua kev nce mus rau ESKD hauv cov neeg mob uas muaj kev hloov pauv los ntawm 3 xyoos (los ntawm 20 txog 23 xyoos).
Raws li kev tiv thaiv lub raum tseem ceeb ntawm ACEI / ARB, kev pom zoo ntawm cov kws tshaj lij hauv tsev thiab txawv teb chaws pom zoo ACEI / ARB raws li kev kho tus qauv rau Alport syndrome. Nws raug pom zoo tias cov txiv neej uas muaj X-txuas Alport syndrome thiab cov neeg mob uas muaj autosomal recessive Alport syndrome pib ACEI / ARB txoj kev kho los ntawm lub sijhawm kuaj mob, thiab cov poj niam uas muaj X-txuas Alport syndrome thiab cov neeg mob autosomal dominant syndrome pib ACEI / ARB kev kho mob thaum microalbuminuria. tshwm sim. Nws yuav tsum tau taw qhia tias tseem tsis muaj kev tshawb fawb soj ntsuam thiab kev soj ntsuam hauv Suav teb tam sim no. Kev tshawb fawb soj ntsuam loj dua yog xav tau los muab cov ntaub ntawv pov thawj ntawm kev siv tshuaj kho mob uas muaj ntau dua nrog cov neeg mob Suav thiab tsim cov qauv thiab cov qauv coj los qhia kev kuaj mob thiab kev kho mob.
Tsis tas li ntawd, inhibition ntawm inflammatory teb los ntawm Nrf2 agonist (Bardoxolone), anti-fibrosis los ntawm Anti-miRNA-21 compound (Lademirsen), endothelin A receptor inhibitor (Atrasentan) thiab dual inhibitor ntawm angiotensin II thiab endothelin A receptor tshiab multi -channel tshuaj xws li (Sparsentan) kom txo qis glomerular siab yog nyob rau hauv kev sim tshuaj, nrog rau cov kev pab cuam noob caj noob ces xws li CRISPR/Cas9 gene editing technology thiab exon skipping therapy, uas tseem yuav coj cov txiaj ntsig rau kev kho mob ntawm cov neeg mob Alport syndrome. yav tom ntej. Kev Cia Siab tshiab.
laminin-sociated raum kab mob
Piv txwv li, laminin 2 (LAMB2) gene mutations ua rau cov qauv tsis zoo ntawm laminin 521, uas tiv thaiv lub cev polymerization ntawm laminin 521 molecules, los yog laminin 521 yog hloov los ntawm lwm hom laminin, uas ua rau kev loj hlob thiab loj hlob ntawm GBM. Kev txawv txav, nce permeability, nrog kev puas tsuaj ntawm podocyte thiab loj proteinuria, uas yog Pierson syndrome.
Pierson Syndrome yog ib qho mob autosomal recessive yam ntxwv kho mob los ntawm nephrotic syndrome nrog neurodevelopmental abnormalities (piv txwv li, hypotonia, nqaij tsis muaj zog) thiab ocular abnormalities.
Tsis tas li ntawd, nyob rau hauv lub raum biopsy, nyob rau hauv kev kuaj fluorescence, tsis muaj kev tiv thaiv kab mob, thiab laminin 2 poob tuaj yeem pom hauv cov neeg mob raug mob; Lub teeb microscopy qhia tau hais tias muaj zog mesangial matrix, thiab podocytes yog qhov hloov pauv, uas tuaj yeem nrog focal segmental Glomerulosclerosis (FSGS) zoo li qhov txhab, tubulointerstitial atrophy, thiab fibrosis; nce mesangial matrix ntawm electron microscopy, diffuse ko taw txheej txheem fusion ntawm podocytes, irregular thickening thiab thinning ntawm GBM, GBM txheej compaction pom.
Hauv kev xyaum kho mob, LAMB2 kev hloov pauv tuaj yeem kuaj pom hauv qee cov neeg mob uas muaj Alport syndrome, thiab LAMB2-S580R kev hloov pauv yuav ua rau kev nce qib ntawm X-txuas tseem ceeb Alport syndrome.
Lwm Hom IV Collagen-Associated Kidney Diseases
Gene mutations ntsig txog IV collagen thiab podocytes kuj nquag tshwm sim hauv FSGS cov neeg mob. Tom qab phiaj xwm vaj huam sib luag ntawm 135 tus neeg laus cov neeg laus uas muaj cov kab mob steroid-resistant nephrotic syndrome (SRNS), nws tau pom tias 14 tus neeg mob (10.4 feem pua) nqa 2 Ntawm lwm cov kab mob sib kis, cov noob muaj feem cuam tshuam txog 56.3 feem pua, thiab hom IV collagen noob. kev hloov pauv suav nrog 43.7 feem pua. Cov neeg nqa khoom muaj qhov pom kev tsis zoo dua li cov uas tsis nqa cov noob hloov pauv.
Collagen type IV gene mutations kuj tuaj yeem tshwm sim hauv tsev neeg IgA nephropathy. Tom qab tag nrho exome sequencing ntawm 46 IgA nephropathy cov tsev neeg, hom IV collagen noob kev hloov pauv tau kuaj pom hauv 9 tus neeg mob (20 feem pua), thiab COL4A3 / A4 heterozygous kev hloov pauv ntau dua.
Ntxiv rau cov kab mob raum hais saum toj no, txij li thaum 1 1 2(IV) tau muab faib rau hauv txhua lub hauv paus hauv qab ntawm lub cev, COL4A1/A2 noob hloov tuaj yeem cuam tshuam rau ntau lub tshuab. Ntxiv nrog rau hematuria thiab lub raum hlwv nyob rau hauv lub raum kab mob, kab mob cerebrovascular (xws li cerebral perforating deformity, kab mob cerebrovascular, thiab lwm yam), ocular txhab (xws li cataracts, retinal hemorrhage, thiab lwm yam), cov leeg nqaij, thiab mob plawv. Yog li ntawd, thaum tus neeg mob pom tias muaj COL4A1 / A2 variant, ib tus yuav tsum tsis txhob tsom rau tus kab mob raum nkaus xwb.
Hauv kev xaus, kev hloov pauv noob muaj txiaj ntsig zoo rau kev kuaj mob thiab kho mob raum thiab cov tsos mob ntawm lub cev. Nws raug nquahu kom ua cov tshuaj ntsuam genetic test rau cov neeg mob uas muaj cov xwm txheej hauv qab no: steroid resistance refractory FSGS, tsev neeg IgA nephropathy, glomerular GBM Layer fracture, thickness tsis sib xws, cov qauv tsis zoo, thiab lub raum tsis ua haujlwm.
Yog xav paub ntxiv:ali.ma@wecistanche.com
