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MicroRNA-499a (rs3746444A/G) gene variant thiab susceptibility to type 2 diabetes-associated end-stage renal disease

MANAL S. FAWZY, et al

Abstract

Mob ntshav qab zib nephropathy (DN) yog qhov muaj feem pheej hmoo loj rau theem kawglub raumkab mob(ESRD). MicroRNAs (miRNAs/miRs) thiab lawv cov kev hloov pauv yuav cuam tshuam rau kev noj qab haus huv thiab kab mob, suav nrog DN. Txoj kev tshawb fawb tam sim no tsom los tshawb xyuas cov koom haum ntawm miRNA-499a gene (MIR499A) A/G noob thaj tsam variant (rs3746444) nrog DN-koom nrog ESRD(theem kawglub raumkab mob)susceptibility nyob rau hauv cov neeg mob ntshav qab zib mellitus thiab txiav txim siab seb puas muaj kev koom tes ntawm cov genotypes sib txawv thiab cov neeg mob lub chaw kuaj mob thiab cov ntaub ntawv kho mob. Ib txoj kev tshawb nrhiav kev tswj xyuas tus kheej tau ua rau 180 tus neeg mob laus uas muaj hom 2 mob ntshav qab zib mellitus. Tag nrho ntawm 90 tus neeg mob nrog ESRD (theem kawglub raumkab mob)Nyob rau tib lub sij hawm hemodialysis raug suav hais tias yog cov mob, thiab 90 hnub nyoog-, poj niam txiv neej- thiab haiv neeg-matched cov neeg mob ntshav qab zib nrog normoalbuminuria raug suav hais tias yog kev tswj hwm. MIR499A genotyping tau ua tiav siv TaqMan Real-Time allele kev ntsuam xyuas kev ntxub ntxaug. Cov txiaj ntsig tau pom tias MIR499A rs3746444*G variant conferred susceptibility rau txoj kev loj hlob ntawm ESRD nyob rau hauv co-dominant [(odds ratio (95 feem pua ​​​​kev ntseeg siab lub sij hawm): 2.49 (1.41-3.89) thiab 2.41 (1.61-6.68g) rau hom thiab ntau hom. Piv txwv li], dominant [2.30 (1.18–3.90)] thiab allelic [1.82 (1.17–2.83)] qauv. Hauv kev xaus, cov txiaj ntsig ntawm txoj kev tshawb fawb tam sim no tau qhia tias MIR499A rs3746444 yuav yog qhov cuam tshuam rau DN-sociated ESRD hauv cov pej xeem txoj kev tshawb no.

Cistanche tuaj yeem kholub raumkab mob

Taw qhia

Mob ntshav qab zib nephropathy (DN) cuam tshuam txog theem kawglub raumkab mob(ESRD) yog kev txhawj xeeb txog kev noj qab haus huv rau pej xeem thoob ntiaj teb (1). Hauv peb lub xyoos dhau los, DN koom nrog ESRD(theem kawglub raumkab mob) has been identified as a major cause for dialysis in several countries, including Saudi Arabia, in which type 2 diabetes mellitus (T2DM) accounts for >33 feem pua ​​​​ntawm tag nrho cov mob ntawm ESRD (1,2). Ntau qhov kev tshawb fawb tau pom zoo tau txheeb xyuas cov noob uas cuam tshuam nrog qhov tshwm sim thiab kev loj hlob ntawm DN, suav nrog cov noob cuam tshuam nrog microRNAs (miRNAs / miRs) (3,4). Cov tsev neeg no ntawm non-coding RNAs yog kev txuag heev, cov ntaub so ntswg tshwj xeeb, thiab luv luv (20-24 nucleotides). miRNAs ua lub luag haujlwm tseem ceeb hauv ntau lub cev thiab cov kab mob pathological hauv tib neeg lub cev, suav nroglub raum. Piv txwv li, upregulation ntawm miR-192, miR-194, miR-204, miR-215, thiab miR-216, thiab downregulation ntawm miR-133a, miR-133b, miR-1d, miR-296, miR-1a, miR -122, thiab miR-124a tau pom nyob rau hauv tib neeglub raum(5). Tsis tas li ntawd, miR-192 tau tshaj tawm tias yog 20-fold siab dua qhia hauv corticalraumcov ntaub so ntswg piv nrog medullaryraumcov ntaub so ntswg, qhov twg nws cuam tshuam rau kev tswj hwm kev thauj mus los ntawm sodium; Tsis tas li ntawd, miR-155 tuaj yeem cuam tshuam qhov kev qhia ntawm angiotensin II receptor type 1, uas tuaj yeem cuam tshuam cov ntshav siab (5,6). Los ntawm kev khi rau mRNA lub hom phiaj, miRNAs muaj peev xwm ua rau muaj kev cuam tshuam kev txhais lus, mRNA destabilization, thiab / lossis degradation (7). Cov thermodynamics ntawm miRNA-mRNA lub hom phiaj kev sib cuam tshuam tuaj yeem cuam tshuam los ntawm ib leeg-nucleotide polymorphisms (SNPs) tshwm sim hauv precursor-miRNA (pre-miRNAs), uas ua rau lub hom phiaj gene dysregulation thiab, tom qab, phenotype variations lossis kab mob susceptibility (8). Lub miRNA-499a noob (MIR499A) yog nyob rau hauv tib neeg myosin hnyav saw 7B plawv cov leeg nqaij gene ntawm chromosome 20q11. Nws yog 122 lub hauv paus khub ntev thiab tau tshaj tawm tias yog tus cim ntawm kev raug mob cardiomyocyte (9). Txawm hais tias tus naj npawb ntawm cov kev tshawb fawb tsom mus rau lub luag haujlwm meej ntawm miR-499a hauv pathogenesis thiab kev loj hlob ntawm ESRD vim DN raug txwv, miR-499a tau raug npaj los cuam tshuam rau ntau yam kev lom neeg, xws li cellular senescence, o, apoptosis, thiab kev tiv thaiv kab mob. teb (10), uas tuaj yeem ua lub luag haujlwm hauv ESRDbiogenesis (Table SI) (11–14). Ntxiv mus, yav dhau los tau tshaj tawm tias miR-499a upregulation tuaj yeem tswj cov tshuaj insulin tsis kam, glycogenesis thiab modulate insulin signaling los ntawm inhibition ntawm phosphatase thiab tensin homolog (15).

Ib qho kev sib txawv (rs3746444), uas nyob hauv thaj tsam miR-499a-3p noob AC(A/G)UCAC ntawm qhov chaw 20: 34,990,448 (GRCh38), tau tshaj tawm tias muaj feem cuam tshuam nrog ntau yam kab mob, tshwj xeeb tshaj yog nyob rau sab hnub tuaj. cov pej xeem, xws li kab mob plawv (9), kab mob autoimmune (16) thiab mob qog noj ntshav (17). Hauv peb txoj kev tshawb fawb yav dhau los, kev tsis txaus ntseeg tseem ceeb ntawm kev nthuav dav miR-499a qib tau txheeb xyuas hauv DM-sociated ESRD tam sim no.(theem kawglub raumkab mob)kev sib tw (18). Yog li, txoj kev tshawb fawb tam sim no tsom los tshawb txog kev sib koom ua ke ntawm MIR499A (A / G) cov noob thaj tsam sib txawv (rs3746444) nrog DN-sociated ESRD susceptibility nyob rau hauv cov neeg mob nrog T2DM thiab txiav txim seb puas muaj kev koom tes ntawm cov genotypes sib txawv thiab cov neeg mob ' cov ntaub ntawv kho mob-lab. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, qhov no yog thawj txoj kev tshawb fawb los tshawb xyuas qhov muaj peev xwm sib koom ua ke ntawm qhov txawv txav nrog ESRD susceptibility nyob rau hauv Middle East tus neeg mob tus qauv.

Cov ntaub ntawv thiab cov txheej txheem

Kawm cov pej xeem.

Tag nrho ntawm 90 tus neeg mob sib law liag nrog T2DM-sociated ESRD(theem kawglub raumkab mob)ntawm hemodialysis tsis tu ncua (peb zaug / lub lim tiam) raug xaiv raws li qhov kev tshawb fawb tam sim no cov neeg mob pab pawg. Cov neeg mob tau tuaj koom lub Nephrology Center ntawm Mohammed bin Saud Al-Kabeer rau lub raum lim ntshav ntawm Arar Central Tsev Kho Mob (Arar, Saudi Arabia). Cov txheej txheem suav nrog / cais tawm rau ESRD pawg neeg mob xaiv tau piav qhia meej hauv peb cov haujlwm dhau los ntawm tib ESRD(theem kawglub raumkab mob)tus neeg mob cohort (18). Cov neeg mob uas muaj kab mob ntev, mob autoimmune, mob qog noj ntshav, thiablub raumkab mobLwm yam tshaj li DM-koom nrog nephropathy (kuaj los ntawm lub raum biopsy raws li cov txheej txheem hauv zos tau txais los ntawm cov qauv thoob ntiaj teb rau kev kuaj mob tsis yog mob ntshav qab ziblub raumkab mob) (19) raug cais tawm. Raws li nws muaj feem ntau tias, thaum kawg, feem ntau ntawm cov neeg mob uas kuaj pom muaj ntshav qab zib thaum ntxov yuav tsim ESRD.(theem kawglub raumkab mob), cov neeg mob T2DM nrog lub sijhawm sib txuam ntawm ntshav qab zib thiab normoalbuminuria (urinary albumin / creatinine ratio,<30 µg/mg)="" (20,21)="" were="" considered="" as="" the="" control="" group.="" all="" biomedical="" research="" involving="" human="" participants="" conformed="" to="" the="" guidelines="" of="" the="" helsinki="" declaration.="" the="" protocol="" of="" the="" present="" study="" was="" approved="" by="" the="" research="" ethics="" committees="" of="" northern="" border="" university="" (approval="" no.="" 6/340/h),="" and="" written="" informed="" consent="" was="" obtained="" from="" all="">

Cistanche tuaj yeem kholub raumkab mob

Laboratory tsom xam.

Kev yoo mov venous kuaj tau sau rau ntawm cov pa dawb thiab ethylenediaminetetraacetic acid-lub tshuab nqus tsev vacuum ua ntej kev lim ntshav thib ob rau cov neeg mob ESRD.(theem kawglub raumkab mob). Cov ntshav tau muab cais los ntawm centrifugation rau 12 min ntawm 1,300 xg ntawm chav tsev kub, tam sim ntawd los ntawm cov raj qub rau kev tshuaj xyuas biochemical siv cov khoom lag luam muaj rau cov piam thaj (cat. No. 44044831190),raumKev kuaj ua haujlwm [creati-nine (cat. no. 4810716190) thiab urea (cat. no. 4460715190)] thiab lipid profileing [tag nrho cov cholesterol (cat. no. 3039773190), triacyl-glycerol (cat. no. 4460715190), c (cat. no. 7528566190) thiab LDL-c (cat. no. 7005717190)] ntawm Cobas Integra Biochemical analyzer (tag nrho Roche Diagnostics GmbH).

Genotyping rau MIR499A (rs3746444). Genomic DNA tau muab rho tawm los ntawm tag nrho cov ntshav siv Wizard Genomic DNA Purification cov khoom siv (cat. No. A1120; Promega Corporation) raws li cov chaw tsim khoom raws tu qauv, ua raws li DNA concentration thiab purity ntsuam xyuas siv NanoDrop ND-1000 spectrophotometer (NanoDrop Technologies; Thermo Fisher Scientific, Inc.) thiab agarose gel (2 feem pua) electrophoresis los ntsuam xyuas DNA kev ncaj ncees. Cov qauv tom qab tau muab khaws cia ntawm -20˚C kom txog thaum lub sijhawm genotyping. MIR499A polymorphism assay (rs3746444, assay ID: C_2142612_30) ​​tau khiav siv TaqMan allele kev ntxub ntxaug ntawm PCR lub sijhawm nrog kev ntsuas zoo raws li tau piav qhia yav dhau los (16). Hauv luv luv, PCR tau khiav hauv 25-µl cov tshuaj tiv thaiv ntim uas muaj gDNA (20 ng) diluted rau 11.25 µl nrog cov dej tsis muaj nucleases, 12.5 µl TaqMan Universal PCR Master Mix (2X) thiab 1.25 µl 20 x TaqMan SNP Assay muab los ntawm tib tus neeg muag khoom. Ib qho piv txwv tsis muaj qauv thiab tsis muaj-polymerase enzyme tau khiav txhua zaus nrog cov qauv kev tshawb fawb raws li kev tswj tsis zoo. Genotyping tau ua nyob rau hauv ib qho kev dig muag rau rooj plaub/tswj xwm txheej. PCR amplification tau ua tiav ntawm StepOne Real-Time PCR System (Applied Biosystems; Thermo Fisher Scientific, Inc.), siv cov xwm txheej hauv qab no: Ob-theem pib tuav (2 min ntawm 50˚C, thiab 10 min ntawm 95˚C) , ua raws li 40-cycle ob-kauj ruam PCR (denaturation rau 15 sec ntawm 95˚C thiab annealing/extension rau 1 min ntawm 60˚C). Kev ntxub ntxaug Allelic tau txiav txim siab los ntawm kev tshuaj xyuas cov ntaub ntawv fluorescence los ntawm txhua qhov kev khiav haujlwm uas siv cov software hu ua automated allele (SDS version 1.3.1; Applied Biosystems; Thermo Fisher Scientific, Inc.; Fig. S1). Tag nrho cov genotype hu tus nqi yog 100 feem pua.

Kev txheeb cais.

Cov qauv loj thiab lub zog suav nrog G power‑3 software (http://www.gpower.hhu.de/) qhia tau tias, nrog rau cov qauv kev kawm tshwj xeeb, kev tso cai yuam kev, kev ua yuam kev =0.05, qhov nruab nrab cuam tshuam loj =0.5, thiab ib qho piv txwv loj ntawm 90/pab pawg, yuav ua tau 91 feem pua ​​​​lub zog ntawm txoj kev tshawb no. Cov ntaub ntawv faib tawm thiab qhov sib txawv ntawm qhov sib txawv tau raug ntsuas los ntawm Shapiro-Wilk test thiab Levene qhov kev xeem, raws li. Cov ntaub ntawv txuas ntxiv tau qhia raws li qhov nruab nrab ± tus qauv sib txawv, thiab cov kev sib txawv categorical tau nthuav tawm raws li kev suav ntau zaus. Cov ntaub ntawv tau muab piv nrog qhov kev xeem χ2, thaum tsis muaj kev sib tw Tub Ntxhais Kawm T-test, ib-txoj kev ANOVA, lossis Kruskal-Wallis kev xeem tau siv los sib piv cov kev sib txawv tsis tu ncua. Qhov sib txawv ntawm qhov pom genotype faib los ntawm Hardy-Weinberg equilibrium tau soj ntsuam siv χ2 goodness-of-fit siv Online Encyclopedia for Genetic Epidemiology (http://www.oege.org/). Genotype-specific adjusted odds ratios (ORs) thiab 95 feem pua ​​​​ntawm kev ntseeg siab (CIs) raug xam rau cov qauv caj ces sib txawv. Txoj kev tshawb no hloov pauv, suav nrog hnub nyoog, poj niam txiv neej, tus naj npawb ntawm hemodialysis zaug, muaj ntshav siab, thiab lub sijhawm ntawm tus kab mob, tau hloov kho. P<0.05 was="" considered="" to="" indicate="" a="" statistically="" significant="" difference.="" spss="" version="" 23="" (ibm="" corp.)="" was="" used="" for="" the="" statistical="">

MIR499A (rs3746444) variant hauv silico tsom xam.

MIR499A (rs3746444) variant hauv silico tsom xam. Gene structural thiab functional tsom xam tau ua siv Ensembl Genomic database (ensembl.org) thiab miRBase.org; Lub hom phiaj kwv yees tau ua tiav siv DIANA-micro T-CDS v5.0 (http://diana.imis.athena innovation.gr/DianaTools/index.php?r=microT_ CDS/index), miRBase (http://www.mirbase.org/) thiab DIANA‑TarBase v7.0 algorithm (http://diana.imis.athena-innovation.gr/DianaTools/index.php ?r=tarbase/index) databases; thiab annotation pawg thiab kev txheeb xyuas kev txhim kho txoj hauv kev tau ua tiav siv miRPath v3.0 (http://www.microrna.gr/miRPathv3) thiab txhua yam tau nthuav dav hauv peb cov kev tshawb fawb yav dhau los (8,12). Kev kwv yees miR-499a lub hom phiaj tau muab piv nrog rau qhov muaj ob qho tib si A thiab G alleles siv cov kev pab cuam miR2Go (http://compbio.uthsc.edu/miR2GO) ntawm qhov nruab nrab hierarchical filtering theem (P<>

Cov txiaj ntsig

Cov yam ntxwv ntawm cov neeg kawm.

Cov yam ntxwv tseem ceeb ntawm cov kev kawm tau sau tseg hauv Table I. Qhov nruab nrab hnub nyoog ntawm cov neeg mob uas muaj ESRD(theem kawglub raumkab mob)yog 46.6 ± 12.3 xyoo rau cov txiv neej thiab 47. 0± 14.7 xyoo rau cov poj niam. Lub sijhawm nruab nrab ntawm kev lim ntshav tau muab piv rau ob leeg poj niam txiv neej hauv cov neeg koom nrog kev tshawb fawb. Tsis muaj qhov sib txawv ntawm kev sib deev tshwj xeeb hauv kev kho mob thiab biochemical cov yam ntxwv ntawm cov neeg koom nrog, tshwj tsis yog cov kev cuam tshuam nrog lipid profile tsis, uas yog qhov phem dua rau cov poj niam cov neeg mob piv rau cov txiv neej (Table I).

MIR499A variant (rs3746444) nyob rau hauv kev kawm pej xeem.

Hauv kev tshawb fawb pej xeem, genotype zaus ntawm MIR499A (rs3746444) SNP ua raws li Hardy-Weinberg equilibrium (P=0.149 hauv kev tswj hwm thiab P=0.398 tus neeg mob). Cov me me allele zaus rau rs3746444*G yog 0.28 thiab 0.42 hauv kev tswj thiab cov neeg mob ESRD(theem kawglub raumkab mob), raws. Qhov sib txawv tseem ceeb hauv MIR499A genotypes tau pom ntawm cov pab pawg kawm. Qhov zaus ntawm GG genotype yog 11.1 feem pua ​​​​hauv kev tswj hwm, piv nrog 20 feem pua ​​​​ntawm cov neeg mob ESRD.(theem kawglub raumkab mob)(P=0.030). Nqa lub rs3746444*G allele tau tshaj tawm ze li ntawm 2-fold nce hauv kev raug rau txoj kev loj hlob ntawm ESRD(theem kawglub raumkab mob), nrog OR (95 feem pua ​​​​CI) ntawm 1.82 (1.17-2.83) nyob rau hauv cov qauv kev sib txuas ntawm cov noob caj noob ces. Raws li qhov tshwm sim, homozygote / heterozygote cov tib neeg (rs3746444 * GG / AG) muaj feem ntau yuav tsim ESRD raws li homozygous / heterozygous piv thiab cov qauv tseem ceeb [GG vs. AA: LOS SIS=2.41, 95 feem pua ​​CI: 1.81-6. ; AG vs. AA: OR=2.49, 95% CI: 1.41-3.89; (AG plus GG) vs. AA: OR=2.30, 95% CI: 1.18-3.90; Table II].

MIR499A variant (rs3746444) thiab chaw kho mob-laboratory yam ntxwv ntawm cov neeg mob ESRD(theem kawglub raumkab mob). Thaum tshawb xyuas qhov sib txawv ntawm cov genotypes ntawm qhov sib txawv ntawm qhov sib txawv thiab kev kho mob thiab biochemical cov yam ntxwv ntawm pawg neeg mob, tsis muaj kev koom tes tseem ceeb, raws li tau pom hauv Table III.

Cov nyhuv ntawm MIR499A (rs3746444) ntawm cov qauv noob thiab kev ua haujlwm.

Txawm hais tias miR-499a tsim ib lub voj plaub hau thib ob nrog kev sib txuas ua ke hauv nws cov qauv (Daim duab S2), cov noob sib txawv tau kwv yees tias yuav raug tsom los ntawm ob qho tib si mature forms synthesized los ntawm ob sab caj npab. Tag nrho ntawm 1,890 noob tau kwv yees tias yuav cuam tshuam los ntawm miR-499a (919 noob los ntawm 3p, 810 los ntawm 5p, thiab 161 noob los ntawm ob qho tib si), raws li tau piav qhia yav dhau los (8). Qhov tseem ceeb tshaj plaws Kyoto Encyclopedia ntawm Genes thiab Genomes (KEGG) txoj hauv kev cuam tshuam nrog miR-499a lub hom phiaj uas tuaj yeem koom nrog DN nce mus rau ESRD(theem kawglub raumkab mob)tau muab sau tseg rau hauv Table IV.

Lub xub ntiag ntawm rs3746444 SNP nyob rau hauv thaj tsam ntawm cov noob ntawm cov neeg caij tsheb miR-499a strand tuaj yeem ua rau muaj kev cuam tshuam ntawm lub hom phiaj thiab tsim cov txheej txheem sib txawv (8,16). Tsis tas li ntawd, nws tuaj yeem ua kom luv luv ntawm qia-voj qauv; Yog li, cuam tshuam rau kev ua haujlwm ntawm tag nrho miRNA.

Peb txoj kev tshawb fawb yav dhau los tau tshaj tawm txog kev tsis zoo ntawm cov kab mob ntawm cov hlab ntshav ntawm miR-499a hauv tib tus neeg mob pawg (18); Yog li ntawd, txoj kev tshawb fawb tam sim no tau tsom mus rau kev txiav txim siab seb cov kab mob ntshav qab zib no puas muaj qhov txawv txav ntawm cov genotypes ntawm tib lub noob. Cov kev tshawb pom, txawm li cas los xij, tsis tau nthuav tawm cov koom haum tseem ceeb ntawm cov genotypes sib txawv ntawm MIR499A (rs3746444) thiab cov qib miR-499a ntshav ntshav kuaj pom yav dhau los siv txoj kev Livak (22) (P=0.173; Fig. 1) .

Cistanche tuaj yeem kholub raumkab mob

Kev sib tham

SNPs tau raug tshaj tawm tias yog hom kev hloov pauv caj ces feem ntau cuam tshuam nrog ntau haiv neeg, kev kis kab mob, thiab cov lus teb rau tus kheej (23). SNPs tuaj yeem cuam tshuam rau miRNA kev nthuav qhia thiab / lossis kev loj hlob ntawm qib ntawm kev sau cov ntawv sau thawj zaug, kev ua haujlwm tom qab luam ntawv ntawm thawj cov ntawv sau tseg lossis ua ntej miRNAs, lossis cuam tshuam rau miRNA-mRNA kev sib cuam tshuam (24).

Txoj kev tshawb fawb tam sim no tau pom tias nqa rs3746444 * G allele tau txais kev cuam tshuam rau ESRD(theem kawglub raumkab mob)in patients with DM compared with non‑carriers under the allelic, co‑dominant, and dominant genetic association models. Results of our previous study demonstrated that the rs3746444 polymorphism results in an A>G mismatch nyob rau hauv lub miR-499a precursor qia cheeb tsam (nyob rau sab nraum lub mature sequence), cuam tshuam rau mR-499a-3p noob cheeb tsam implicated nyob rau hauv qhov tseeb miRNA-mRNA khi, nrog rau kev cuam tshuam tom qab thiab tsim ntawm ntau lub hom phiaj (8). Cov neeg nqa khoom ntawm homozygote genotypes (AA lossis GG) muab ob daim ntawv paub tab, miR-499a-5p thiab miR-499a-3p * A lossis * G, raws li, nrog rau txhua tus muaj nws cov vaj huam sib luag ntawm cov hom phiaj. Hauv kev sib piv, cov neeg nqa khoom heterozygous (AG) tsim peb daim ntawv paub tab, miR-499a-5p, ‑3p * A, thiab ‑3p * G, nrog rau peb lub npe ntawm cov hom phiaj. Cov kev soj ntsuam hauv silicon ntawm txoj kev tshawb fawb tam sim no tau qhia tias muaj qhov sib txawv ntawm cov alleles no tuaj yeem cuam tshuam thiab tsim 667 thiab 744 noob hom phiaj, feem. Ntawm cov validated noob hom phiaj uas tau raug soj ntsuam yog nucleolar protein 4, nuclear receptor interacting protein-1, Bcl-2-zoo li protein 14, chemokine (C-C motif) ligand 8, thiab kev sib deev-txiav cheeb tsam Y-box 4 (20) . Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, qhov no yog thawj txoj kev tshawb fawb los tshawb xyuas MIR499A rs3746444 variant rau ESRD susceptibility nyob rau hauv cov neeg mob nrog DM nyob rau hauv ib qho piv txwv ntawm Middle East cov pejxeem. Raws li qhov kev tshawb pom ntawm qhov kev tshawb fawb tam sim no, Misra et al (25) tau tshaj tawm tias heterozygous thiab homozygous genotypes ntawm MIR-499A rs3746444 tau muab kev pheej hmoo rau ESRD txoj kev loj hlob, uas tau tshwm sim los ntawm lwm yam kab mob sib nrug ntawm DN, thiab tej zaum yuav cuam tshuam nrog ib qho Yuav luag 3-fold nce kev pheej hmoo rau kev tsis lees txais cov allograft mob hauv North Indian cov pej xeem (25).

Muab hais tias SNPs hauv pre-miRNAs tuaj yeem hloov pauv miRNA kev ua thiab / lossis kev qhia, ntawm kev txheeb xyuas kev sib koom ua ke ntawm MIR499A polymorphism nrog miR-499a plasma circulating qib thiab txawv chaw kho mob-lab tus yam ntxwv ntawm cov neeg mob, tsis muaj kev koom tes tseem ceeb, raws li tau piav qhia dhau los. Nws tau pom zoo tias muaj qhov sib txawv ntawm miR-499a tuaj yeem cuam tshuam rau cov thermodynamics ntawm RNA-RNA kev sib cuam tshuam thiab kev sib raug zoo ntawm miRNA no los ntawm kev cuam tshuam nrog kev sib raug zoo rau lub hom phiaj mRNAs, yog li ua rau muaj kev tsis sib haum xeeb ntawm cov hom phiaj uas kho cov kab mob cuam tshuam rau ESRD(theem kawglub raumkab mob)yam tsis muaj kev cuam tshuam rau tus txheeb ze qhia thiab / lossis kab mob phenotype (22). Cov kev soj ntsuam hauv silico ntawm txoj kev tshawb fawb tam sim no tau nthuav tawm qee qhov tseem ceeb ntawm KEGG txoj hauv kev uas cuam tshuam nrog miR-499a lub hom phiaj uas tuaj yeem koom nrog DN nce mus rau ESRD (26-32). Piv txwv li, txoj kev (TGF- 1) tau cuam tshuam hauv DN etiopathology (26,28). Txoj kev TGF- 1 qhib txoj hauv kev tseem ceeb, suav nrog PI3K / AKT txoj hauv kev uas kho cov phosphorylation thiab inactivation ntawm transcriptional FOXO, ua rau oxidant kev nyuaj siab, mesangial cell expansion, thiab tsub zuj zuj ntawm extracellular matrix proteins, tseem ceeb Cheebtsam ntawm DN-kev koom tes chronic.raumkab mob (26). Upregulation ntawm epidermal growth factor receptor (ErbB) tyrosine kinase kev ua haujlwm yog qhov tseem ceeb hauv kev kho ntau yam mob ntshav qab zib, suav nrog rau lub raum pathologies, plawv fibrosis, thiab vascular dysfunction (29). Tsis tas li ntawd, lub luag haujlwm ntawm TNF txoj hauv kev hauv kev nce qib ntawm DN hauv cov nas mob ntshav qab zib thiab cov qauv nas tau pom tseeb. Piv txwv li, siv TNF receptor-2 fusion fusion protein uas muaj kuab heev tau tshaj tawm los txhim kho cov theem pib ntawm DN hauv DM qauv ntawm KK-Ay nas (30). Tsis tas li ntawd, TNFR-Fc TNF inhibitor tau pom tias txo qis lub raum hypertrophy yam tsis muaj kev cuam tshuam cov metabolic profile hauv cov nas uas muaj ntshav qab zib (31). mTOR tau cuam tshuam rau kev tswj cov glomerular podocyte function-tion; nce kev ua haujlwm tau ua rau glomerular hypertrophy thiab hyperfiltration cuam tshuam nrog kev nce qib DN (32).

Qhov tseem ceeb, txoj hauv kev tau hais los saum no tau tsom mus rau ntau qhov kev sim tshuaj ntsuam xyuas kom paub tseeb tias lawv qhov kev cuam tshuam kho mob hauv DN (29,30,33,34). Ziyadeh et al (33) tau tshaj tawm txog kev txhim kho hauv glomerular pom tus nqi raug ntxias los ntawm monoclonal anti-TGF- antibody hauv db/db cov nas mob ntshav qab zib (33). Tsis tas li ntawd, kev kho mob mus sij hawm ntev ntawm streptozotocin-induced ntshav qab zib nas nrog AG825, ib qho tshwj xeeb inhibitor ntawm receptor tyrosine-protein kinase ErbB-2, tau tshaj tawm kom kho qhov hyperreactivity ntawm perfused mesenteric vascular txaj rau norepinephrine thiab attenuated teb. carbachol (29) . Inhibition ntawm TNF- nrog cov soluble TNF receptor (TNFR)2 fusion protein, etanercept, txhim kho kev loj hlob ntawm cov theem pib ntawm DN hauv cov qauv ntshav qab zib tsim hauv KK-A(y) nas, feem ntau los ntawm inhibition ntawm cov tshuaj tiv thaiv. Kev ua ntawm lub raum TNF- TNFR2 txoj hauv kev (30). Tsis tas li ntawd, rapamycin, thawj cov lus tshaj tawm los tiv thaiv mTOR, inhibits cov piam thaj-induced phosphorylation ntawm p70S6 kinase thiab nws cov substrate, S6 ribosomal protein, nyob rau hauv mesangial hlwb, attenuating morphological thiab functional ntshawv siab ntawm cov ntshav qab zib.lub raumhauv T2DM nas qauv (34).

Raws li qhov kev tshawb pom ntawm qhov kev tshawb fawb tam sim no, Ciccacci li al (35) tau qhia txog kev koom tes ntawm miR-499a hauv DN susceptibility hauv Italian T2DM cohort (35). Cov txiaj ntsig ntawm qhov kev tshawb fawb tau hais los saum no tau qhia tias lub koom haum no yog vim muaj kev cuam tshuam ntawm miR-499a ntawm ob tus neeg ua si apoptotic, calcineurin thiab dynamin-related protein, uas yog miR-499a dysregulation ua rau mitochondrial tsis ua haujlwm thiab cell apoptosis, uas tuaj yeem ua rau muaj kab mob. (33). Qhov tseem ceeb, cov txheej txheem tom kawg tau cuam tshuam nrog DN (36,37), uas tuaj yeem txhawb nqa kev koom tes ntawm miR-499a variant nrog ESRD.(theem kawglub raumkab mob)susceptibility nyob rau hauv lub cohort tam sim no. Txawm li cas los xij, kev tshawb fawb ntau ntxiv uas muaj cov pab pawg ywj pheej loj dua nrog ntau haiv neeg yuav tsum tau lees paub qhov kev tshawb pom ntawm qhov kev tshawb fawb tam sim no.

Hauv kev xaus, rau qhov zoo tshaj plaws ntawm peb txoj kev paub, txoj kev tshawb fawb tam sim no yog thawj zaug los tawm tswv yim txog qhov cuam tshuam ntawm MIR499A A / G cov noob thaj tsam variant (rs3746444) ntawm DN-sociated ESRD(theem kawglub raumkab mob)kev raug mob. Nws tuaj yeem suav nrog hauv cov npe ntawm cov noob caj noob ces uas tuaj yeem txhawb nqa tus neeg mob-kev pheej hmoo stratification thiab kev ntsuas kev tiv thaiv ntxov. Txawm li cas los xij, nws tsim nyog sau cia tias qhov cuam tshuam ntawm lwm tus neeg muaj peev xwm tsis tuaj yeem txiav txim siab, xws li raug cuam tshuam rau ntau qhov chaw ib puag ncig (xws li hom kev kho mob lossis khoom noj khoom haus) thiab lwm yam caj ces. Ntxiv cov qauv loj dua thiab cov kev tshawb fawb rov qab mus sij hawm ntev, tshwj xeeb tshaj yog nyob rau hauv cov pej xeem nrog ntau haiv neeg, raug lav. Cov kev tshawb fawb ua haujlwm tseem yuav tsum tau lees paub lub luag haujlwm ntawm miR-499a hauv DN-sociated ESRD etiopathology.

Cistanche tuaj yeem kholub raumkab mob

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