Tsis ntev los no Advances nyob rau hauv Diabetic raum Kab Mob: Los ntawm raum Injury rau raum Fibrosis Part 1
Apr 19, 2023
Abstract:
Mob raum mob ntshav qab zib mellitus (DKD) yog qhov ua rau muaj kab mob raum ntev thiab kab mob raum kawg. Cov keeb kwm ntawm DKD suav nrog glomerular hyperfiltration, nce qib albuminuria, txo qis tus nqi glomerular pom, thiab, thaum kawg, lub raum tsis ua haujlwm.
Nws paub tias DKD cuam tshuam nrog kev hloov pauv hauv metabolic los ntawm hyperglycemia, ua rau glomerular hypertrophy, glomerulosclerosis, thiab tubulointerstitial o thiab fibrosis. Hyperglycemia kuj tseem paub tias ua rau kev hloov pauv hloov pauv hloov pauv hloov pauv. Txawm li cas los xij, cov txheej txheem ntxaws ntxaws uas cuam tshuam rau qhov pib thiab kev loj hlob ntawm DKD tseem tsis pom. Hauv kev tshuaj xyuas no, peb tham txog kev nce qib tsis ntev los no txog cov txheej txheem pathogenic koom nrog hauv DKD.
Qhov tshwm sim ntawm hyperglycemia nyob rau hauv cov neeg mob uas muaj kab mob raum ntev kuj tseem siab, vim hais tias lub raum yog ib qho tseem ceeb ntawm cov metabolism hauv qabzib, thiab cov neeg mob ntshav qab zib feem ntau nrog rau lub raum puas. Tsis tas li ntawd, hyperglycemia tseem tuaj yeem ua rau cov cell membrane permeability ntawm lub raum tubular epithelial hlwb, cuam tshuam rau lub cev ua haujlwm ntawm lub raum tubular, thiab ua rau mob raum mob hnyav ntxiv.
Hauv peb txoj kev tshawb fawb, peb pom tias Cistanche muaj cov txiaj ntsig kho mob rau cov kab mob raum ntev, thiab Cistanche tuaj yeem txhawb nqa lub raum thiab txhawb nqa yin, yog li tswj hwm lub raum ua haujlwm. Cov neeg mob uas mob raum mob feem ntau nrog rau lub raum tsis txaus. Cistanche tuaj yeem txhim kho lub raum atrophy thiab glomerulosclerosis hauv cov neeg mob raum, thiab tib lub sijhawm txhim kho cov metabolism hauv lub raum.
Ntsiab lus:
mob ntshav qab zib raum; mob; albuminuria; fibrosis; glomerulosclerosis.
1. Mob ntshav qab zib mellitus thiab ntshav qab zib raum kab mob
Tam sim no, ntau dua 400 lab tus tib neeg nyob nrog ntshav qab zib mellitus (DM) thoob ntiaj teb. Tus lej no yuav tsum nce mus rau 600 lab los ntawm 2035 [1]. DM cuam tshuam rau tib neeg ntawm txhua lub hnub nyoog, tsis hais poj niam txiv neej, haiv neeg, qib kev kawm, lossis nyiaj txiag [2]. Ntawm cov neeg mob DM, 20 feem pua ntawm cov neeg mob tuaj yeem ua rau mob ntshav qab zib mellitus (DKD) [3], uas paub tias cuam tshuam los ntawm cov caj ces thiab ib puag ncig thiab cuam tshuam los ntawm microvascular thiab macrovascular hloov pauv, suav nrog kev sib sau ntawm extracellular matrix thiab hypertrophy thiab fibrosis ntawm lub cev. lub raum glomeruli thiab interstitium [4,5].
Thaum pib, cov neeg mob DKD feem ntau pom cov tsos mob ntawm microalbuminuria, nrog 30 mus rau 300 mg ntawm albumin tawm ib hnub; Qhov no maj mam loj hlob mus rau hauv macroalbuminuria, nrog ntau tshaj 300 mg ntawm albumin tawm ib hnub tom qab cov kab mob theem [6]. Qhov kev phom sij rau txhua qhov kev tuag hauv DKD cov neeg mob nrog macroalbuminuria yog 1.83, piv rau 1.46 rau cov neeg mob uas muaj normoalbuminuria [7].
Zuag qhia tag nrho, kev sib cuam tshuam ntawm cov txheej txheem metabolic, cov txheej txheem epigenetic thiab nonnepigenetic, thiab kev tswj hwm kev hloov pauv tau koom nrog hauv kev txhim kho thiab kev loj hlob ntawm DKD, thiab tsuas yog ob peb xyoos dhau los no muaj peev xwm txheeb xyuas cov tshuaj, xws li sodium-glucose cotransporter 2 (SGLT2) inhibitors uas tuaj yeem ua tau zoo tiv thaiv hypoglycemia thiab txhim kho lub raum cov txiaj ntsig [8,9]. Tsis tas li ntawd, endothelin-1 (ET-1) tau cuam tshuam nrog vasoconstriction, mob raum raug mob, mesangial hyperplasia, glomerulosclerosis, fibrosis, thiab o, thiab yog li endothelin receptor antagonists tau npaj los ua kev kho mob rau DKD [ 10].
2. Kev cuam tshuam ntawm Hyperglycemia ntawm Kev Kho Mob Ntshav Qab Zib-Mediated Cellular Alterations
Vim yog qhov kev qhia tsis raug cai ntawm cov piam thaj thauj mus los, cov qib siab ntawm cov piam thaj hauv lub cev yuav ua rau kom cov piam thaj hauv cov ntshav nce siab [11], ua rau cov piam thaj hloov pauv mus rau fructose 6-phosphate thiab hexosamine metabolic pathways [12].
Yog li, hyperglycemia feem ntau ua rau cov khoom lag luam qib siab glycation kawg (AGEs) thiab cov pa oxygen reactive (ROS), uas cuam tshuam nrog kev loj hlob ntawm DKD. AGEs yog tsim los ntawm nonenzymatic glycation cov tshuaj tiv thaiv ntawm kev txo cov suab thaj thiab amino acids, lipids, los yog DNA, thiab muaj feem xyuam nrog cov qib siab ntawm ROS ntau lawm [13]. ROS yog tsim thaum lub sij hawm mitochondrial oxidative metabolism thiab tom qab raug xenobiotics thiab cytokines, los ntawm cov tshuaj tiv thaiv catalyzed los ntawm NADPH oxidase, nitric oxide synthase, thiab xanthine oxidase [14], thiab ntau dhau ROS yuav ua rau oxidative kev nyuaj siab thiab cell puas. Cov kev tshawb fawb yav dhau los tau pom tias kev txwv kev tsim cov AGEs thiab ROS ua haujlwm tau zoo ua rau kev loj hlob ntawm DKD [15].
Tsis tas li ntawd, ROS paub tias yuav qhib lub Janus kinase teeb liab transducers thiab activators ntawm txoj kev transcription (JAK-STAT), thiab kev sim hauv cov qauv nas ntshav qab zib tau pom tias cov kev xaiv ntawm JAK2 hauv glomerular podocytes nce qhov ua haujlwm thiab cov yam ntxwv ntawm DKD. [16]. Tsis tas li ntawd, nyob rau hauv cov ntaub so ntswg ntawm lub raum ntawm cov neeg mob DKD, tau pom muaj kev qhia ntau ntxiv ntawm ntau tus neeg hauv tsev neeg JAK-STAT tau pom [17].
Nyob rau hauv cov ntshav qabzib siab, ROS yog tsim los ntawm qib siab, thiab qhov no tuaj yeem ua rau mob ntshav qab zib mellitus [18,19]. Kev tsim tawm ntau dhau ntawm ROS feem ntau yog vim qhov ua kom muaj hluav taws xob thauj cov saw hlau thiab electron to ntawm NADH dehydrogenase hauv mitochondria [20]. Kev poob ntawm mitochondrial tswj cuam tshuam rau lub raum kev noj qab haus huv vim tias mitochondria yog qhov tseem ceeb rau ROS tsim, apoptosis, thiab metabolism. Xws li ROS ntau dhau lawm paub tias ua rau DNA puas [21], thiab qhov no ua rau ua rau poly-ADP ribose polymerase-1 (PARP-1) ua kom inhibit glyceraldehyde 3-phosphate dehydrogenase (G3PDH. ) muaj nuj nqi [22,23], uas ua rau tsub zuj zuj ntawm glycolytic metabolites.
Qhov no tom qab ntawd txhawb cov synthesis ntawm polyol, hexosamine, thiab diacylglycerol (DAG), ua kom cov protein kinase C (PKC) txoj hauv kev, thiab tsim cov AGEs [24]. Kev sib cuam tshuam ntawm AGEs thiab lawv cov RAGE receptors ntxiv txhawb kev tsim tawm ntau dhau ntawm ROS thiab ua kom NF-κB, uas tom qab ntawd txhawb kev nthuav tawm ntawm cov noob caj ces, ua rau nce qib ntawm interleukin (IL)-6, qog necrosis. factor- (TNF- ), thiab monocyte chemoattractant protein-1 (MCP-1) [25–27]. Ua ke nrog oxidative kev nyuaj siab, endoplasmic reticulum (ER) kev ntxhov siab, thiab cov txheej txheem inflammatory tshwm sim los ntawm qib qabzib siab, qhov muaj nitric oxide (NO) txo qis thiab angiogenesis tsis zoo, uas tuaj yeem ua rau endothelial tsis ua haujlwm hauv lub raum [28].
Kev ua kom txoj hauv kev hexosamine los ntawm qib qabzib siab tuaj yeem cuam tshuam cov teeb liab hloov pauv, hloov pauv cov noob, kev muaj sia nyob ntawm tes, thiab proteasome-mediated degradation, thiab txhawb nqa hyperglycemia-vim vascular puas tsuaj [29]. Nws paub tias cov ntshav qabzib siab txhawb nqa kev sib sau ntawm extracellular matrix (ECM) [30] thiab txhawb kev qhia ntawm DKK1, Kremen -2 receptor, hloov pauv kev loj hlob ntawm beta (TGF- ), thiab fibrotic yam hauv mesangial. hlwb [31], uas thaum kawg nce mus rau kev puas tsuaj rau lub glomerular filtration barrier ua rau DKD.
Cov neeg mob DKD thiab DM tau paub tias muaj kev cuam tshuam zoo rau cov txiaj ntsig ntawm cov hlab plawv, ib feem ntawm kev ua kom lub renin-angiotensin-aldosterone system (RAAS). RAAS tswj cov ntshav siab, ntsev tshuav, thiab cov kua dej homeostasis [32], thiab RAAS thaiv nrog ACE inhibitors (ACEI) lossis angiotensin receptor blockers (ARB) feem ntau yog siv los hloov kho hyperfiltration xeev thiab ncua kev loj hlob ntawm lub raum kab mob [33]. Cov tshuaj uas tswj cov ntshav siab (lisinopril) thiab hyperglycemia (empagliflozin) kuj tau pom tias yuav txhim kho lub cev thiab cov kab mob histopathological ntawm cov kab mob raum hauv tus nas qauv ntawm kev kub siab-kub nce DKD [34]. Ntxiv mus, kev kho mob nrog N-acetyl-serylaspartyl-proline (Ac-SDKP), ib txwm tshwm sim immunomodulatory thiab angiogenic peptide tsuas yog tsim los ntawm enzymatic hydrolysis uas muaj meprin- thiab prolyl oligopeptidase, tau pom tias yuav txhim kho qhov kawg ntawm lub cev los ntawm kev txo qhov mob thiab fibrosis thiab txhawb nqa angiogenesis [35].
Cov txiaj ntsig zoo ntawm kev xaiv mineralocorticoid receptor antagonist (MRA) eplerenone ntawm lub raum cov txiaj ntsig tsis zoo xws li proteinuria tau raug sau tseg rau qee lub sijhawm, thiab kev siv zog los tsim MRAs raws li kev kho mob ntxiv kom txo tau txoj kev pheej hmoo ntawm DKD [36,37]. Dipeptidyl peptidase-4 (DPP-4) inhibitors feem ntau siv rau kev kho mob ntshav qab zib hom 2 kuj tau pom tias tiv thaiv kev mob raum mob ntshav qab zib los ntawm ntau lub tswv yim; Piv txwv li, inhibition ntawm DPP-4 los ntawm linagliptin txo cov rog rog-txog insulin tsis kam thiab o los ntawm kev tswj hwm ntawm M1 / M2 macrophage xwm txheej, thiab tau ntxiv tuaj yeem txo oxidative kev nyuaj siab thiab mob raum mob ntshav qab zib [38].
Glycosuria induces osmotic diuresis thiab feem ntau tshwm sim hauv cov neeg mob DM thaum cov kua qabzib lim dej ntau dhau lub peev xwm ntawm lub raum tubular reabsorption. SGLT2 inhibitors yog ib chav kawm ntawm cov tshuaj uas hloov kho lub cev tseem ceeb ntawm nephron thiab tuaj yeem txo cov ntshav qab zib los ntawm kev ua rau lub raum tshem cov piam thaj hauv lub cev los ntawm cov zis. SGLT2 inhibitors tseem tuaj yeem pab rov ua haujlwm rau SIRT3, mitochondrial NAD ntxiv rau -dependent deacetylase uas tuaj yeem cuam tshuam kev hloov pauv ntawm epithelial-mesenchymal (EMT) thiab lub raum fibrosis [39], uas yog suppressed los ntawm qib qabzib siab. Kev kho mob nrog cov inhibitors uas thaiv acetylation-mediated STAT3 khi kuj tau pom tias txo cov proteinuria thiab lub raum puas hauv db/db mob ntshav qab zib nas qauv.
3. Genetic Pathways Associated with DKD
Glomeruli yog lub hauv paus lim dej ntawm lub raum thiab muaj cov hlab ntsha capillary uas tuaj yeem lim ntshav plasma thiab tso zis [40]. Txhua lub glomerulus muaj cov hlwb mesangial, podocytes, tubular cells, thiab hauv qab daus daim nyias nyias, txhua yam ua ke los tswj kev ua haujlwm zoo li qub (Daim duab 1). Mesangial hlwb suav txog 30-40 feem pua ntawm tag nrho cov hlwb hauv lub glomerulus [41] thiab yog lub luag haujlwm rau tshem tawm cov kab mob hauv lub cev thiab cov protein sib sau los ntawm cov ntshav ntim hauv qab daus [42].
Daim duab 1. Cov yam ntxwv glomerular hloov pauv thiab cov txheej txheem ntawm cov proteinuria hauv cov ntshav qab zib raum. Cov yam ntxwv glomerular hloov pauv hauv cov kab mob raum mob ntshav qab zib mellitus (DKD) suav nrog glomerular hauv qab daus daim nyias nyias (GBM) thickening thiab mesangial expansion (vim nce mesangial matrix thiab nce mesangial cell loj los ntawm hypertrophy). Cov kev hloov pauv no tau tsav los ntawm hyperglycemia, thiab tuaj yeem ua rau muaj proteinuria yog tias tsis kho. Dashed xub qhia mesangial expansion ua rau glomerular hyperfiltration.
Podocytes yog cov hlwb tshwj xeeb ntawm epithelial uas npog sab nrauv ntawm lub hauv paus membrane [43], thiab hauv cov neeg laus, lawv tau sib txawv thiab tsis rov ua dua. Yog li ntawd, ntau tshaj 20 feem pua poob ntawm podocytes los yog kev puas tsuaj ntawm glomerular filtration barrier qauv tuaj yeem ua rau lub glomerulus puas thiab ua rau cov proteinuria [44]. Nws paub tias hyperglycemia tuaj yeem ua rau apoptosis, detachment ntawm glomerular qab daus daim nyias nyias, thiab poob ntawm glomerular podocytes, mesangial hypertrophy, matrix tsub zuj zuj, thiab hauv qab daus membrane thickening, tag nrho cov cim ntawm DKD thaum ntxov [45], thiab tuaj yeem ua tiav rau glomerular fibrosis. thiab proteinuria [46] (Daim duab 1).
3.1. Lub luag haujlwm ntawm Hyperglycemia hauv Glomerular Fibrosis
Kev raug mob mus sij hawm ntev thiab cov txheej txheem kho qhov txhab tsis zoo, nrog rau ntau dhau ntawm cov cellular matrix deposition, yog cov tsav tsheb tseem ceeb ntawm lub raum fibrosis. Myofibroblasts tau xav tias yog cov nquag ua haujlwm fibroblast phenotype nyob rau hauv lub raum fibrosis [47], thiab ntau qhov chaw paub ntawm myofibroblasts tsim matrix, suav nrog cov neeg ua haujlwm nyob hauv fibroblasts, sib txawv pericytes, recruited circulating fibroblasts, thiab mesenchymal hlwb hloov los ntawm macrophages, tubular derived. hlwb los ntawm EMT, los yog hloov los ntawm endothelial hlwb (EC) los ntawm endothelial-mesenchymal hloov (EndMT) [48]. Tsis tas li ntawd, cov kab mob inflammatory thiab cytokines, nrog rau cov kev cuam tshuam ntawm kev taw qhia, txhua tus ua lub luag haujlwm tseem ceeb hauv kev ua kom fibroblast [49].
Nthuav fibrosis ntawm glomerular microenvironment, tshwj xeeb tshaj yog cov hlwb mesangial, yog lub cim ntawm DKD, thiab cov fibrosis ntawm mesangial hlwb yog ze rau kev ua kom TGF- 1 txoj kev taw qhia, uas txhawb nqa fibroblast activation thiab txawv txav ntawm cov fibrotic synthesis. matrix nyob rau hauv mesangial hlwb [50]
Tsis tas li ntawd, TGF- 1 txhawb nqa lub raum cell proliferation thiab sib txawv, synthesis ntawm extracellular matrix [51], thiab raum tubular epithelial cell EMT, uas yog ib qho tseem ceeb rau kev loj hlob ntawm tubulointerstitial fibrosis [52,53]. Zoo li, cov kev hloov pauv tsis zoo no hauv cov hlwb mesangial, cov hlwb endothelial, thiab podocytes tuaj yeem cuam tshuam, thiab hyperglycemia kuj tseem paub tias cuam tshuam rau cov podocyte-glucocorticoid receptor signaling txoj hauv kev los ua rau EndMT thiab ua rau glomerular fibrosis hauv DM.
Glomerular fibrosis kuj tseem cuam tshuam nrog kev ua haujlwm ntawm Wnt / -catenin signaling, uas hloov TGF- 1-mediated fibrosis hauv mesangial hlwb [54] thiab tuaj yeem qhib glycogen synthase kinase-3 (GSK-3 ) signaling [55] thiab induce apoptosis ntawm mesangial hlwb [56]. Ib txoj kev tshawb fawb yav dhau los tau pom tias GSK-3 phosphorylation txo qis fibroblast activation thiab kev loj hlob ntawm fibrosis hauv nas, tab sis Wnt / -catenin signaling ua rau inhibit qhov no [57]. Hloov pauv, qhov inhibition ntawm Wnt signaling los ntawm DKK1 txo -catenin phosphorylation thiab attenuated TGF{12}} qhia kom txo cov fibrosis ntawm mesangial hlwb [31].
Lwm qhov kev koom tes hauv DKD yog cannabinoid receptor 1 (CB1R) [55], uas ua rau kev nthuav tawm ntawm cov tshuaj hormone receptor peroxisome proliferator-activated receptor 2 (PPAR 2); Tom qab kev khi ntawm adipocyte-specific nuclear cov tshuaj hormones rau PPAR 2 tom qab ntawd ua rau kev hloov pauv ntawm cov noob koom nrog hauv adipogenesis, suav nrog aP2, FGF1, FGF21, thiab CD36 [56], thiab txhawb nqa cov tshuaj insulin hauv lipid metabolism [56]. Ib txoj kev tshawb fawb yav dhau los tau pom tias overexpression ntawm PPARs muaj feem cuam tshuam nrog cov kab mob metabolic, uas ua rau muaj kev hloov pauv hauv lipid metabolism thiab tsub zuj zuj ntawm lub cev rog, uas ua rau DKD thiab nce kab mob hnyav [57].
Nyob rau hauv cov xwm txheej hyperglycemic, CB1R paub tias cuam tshuam rau cov metabolism thiab ua rau cov tshuaj insulin tsis kam ua rau DKD hnyav dua. CB1R kuj txhawb kev qhia cov proteins uas cuam tshuam nrog rau lub raum fibrosis ua rau DKD ua phem, suav nrog cov uas ua rau Ras thiab ERK signaling, transcription factor c-Jun, o regulator SOCS3, thiab proinflammatory cytokines IL-1 thiab fibrotic matrix fibronectin. [58].
3.2. Hyperglycemia-Induced Glomerular Dysfunction thiab Proteinuria
Proteinuria yog ib qho mob ntawm cov protein ntau ntxiv hauv cov zis thiab yog ib qho cim ntawm lub raum puas. Nws paub tias hyperglycemia-induced mitochondria fission nce qhov tsim ntawm ROS ua proteinuria thiab txhawb apoptosis hauv podocytes thiab raum microvascular endothelial hlwb [59,60]. Cov txheej txheem no yog kho los ntawm dynamin-related protein-1 (Drp1) [59], thiab kev tshawb fawb yav dhau los tau pom tias Drp1 hloov mus rau hauv mitochondria yog kho los ntawm phosphorylation thiab kev nrhiav neeg los ntawm Rho-txuas coiled-coil uas muaj protein ntau kinase 1 ( ROCK1) [59], yog li piav qhia vim li cas qhov kev qhia ntawm ROCK1 hauv cov nas mob ntshav qab zib txhawb nqa glomerular apoptosis thiab mitochondrial ROS ntau lawm.
Tsis tas li ntawd, hyperglycemia-induced qhia ntawm lub raum hedgehog interacting protein (Hhip) nyob rau hauv glomerular endothelial cells yuav ua rau cov fibrosis thiab apoptosis ntawm cov hlwb no [61], thiab Hhip theem kuj tau nce siab nyob rau hauv thaum ntxov DKD ntawm cov nas thiab tib neeg, txawm tias ua ntej. Kev txhim kho ntawm microalbuminuria [62] Dhau li ntawm mitochondrial fission, ua kom lub Notch signaling txoj kev yog paub los txhawb txoj kev loj hlob ntawm glomerular kab mob, nrog rau cov proteinuria. Ib txoj kev tshawb fawb tau pom tias qhov intracellular domain ntawm Notch1 activates vascular endothelial kev loj hlob yam (VEGF) induce podocyte apoptosis thiab ua rau proteinuria [63]. Ib txoj kev tshawb fawb yav dhau los kuj tau qhia tias inhibition ntawm txoj kev no tiv thaiv nas nrog proteinuria [64].
Lwm txoj hauv kev qhia txog kev cuam tshuam nrog proteinuria suav nrog txoj hauv kev Wnt/ -catenin; Kev nthuav qhia siab ntawm Wnt / -catenin cov ntawv sau thiab cov proteins tau pom nyob rau hauv cov podocytes ntawm DKD cov neeg mob thiab DKD nas qauv, thaum lub sij hawm ruaj khov ntawm Wnt / -catenin noob nyob rau hauv podocytes ntawm transgenic nas tau pom tias induce albuminuria [65].
Tsis tas li ntawd, hyperactivation ntawm mTOR paub tias yuav ua rau cov kab mob podocyte hypertrophy thiab apoptosis ntawm podocytes, uas ua rau muaj kab mob glomerular thiab proteinuria [66,67]. Nws kuj tseem paub tias txo qis nephrin qhia tau koom nrog hauv hyperglycemia-induced albuminuria [68,69]. Nephrin yog ib qho transmembrane protein nrog extracellular domains uas txuas cov txheej txheem ko taw ntawm podocytes thiab yog qhov tseem ceeb rau kev ua haujlwm zoo ntawm lub raum pom teeb meem. Podocytes paub tias muaj cov qauv actin cytoskeleton complex, thiab kev faib tawm ntawm cov actin cytoskeleton thiab kev cuam tshuam ntawm cov qauv no tau paub tias yuav txo qis nephrin qhia [70]; Piv txwv li, Rac1 thiab Cdc42 paub los tswj cov kev hloov pauv ntawm cov actin cytoskeleton [71], thiab kev tshem tawm ntawm lawv cov noob tau pom los txo qis nephrin qhia thiab induce albuminuria hauv nas [72].
3.3. Hyperglycemia thiab Albuminuria hauv lub raum Tubular Cell Fibrosis
DKD yog zoo sib xws nrog cov fibrosis ntawm lub raum tubular epithelial hlwb [73], uas yog cov epithelial hlwb nyob rau ntawm txheej txheej ntawm lub raum tubule uas ua rau reabsorb qabzib, amino acids, thiab lwm yam tshuaj nyob rau hauv cov zis [74]. Ib txoj kev tshawb fawb yav dhau los tau pom tias muaj cov piam thaj ntau lossis qib albumin tuaj yeem ua rau lub raum tubular epithelial cell fibrosis, thiab qhov no tau cuam tshuam nrog kev nthuav dav ntawm MCP-1, PAI-1, thiab TGF{{4} } raws li qhov tshwm sim ntawm hyperglycemia-induced ROS ntau lawm [75]; Lub raum fibrosis tuaj yeem tiv thaiv tau yog tias cov noob profibrotic raug txwv [76].
Tsis tas li ntawd, fibrosis ntawm lub raum tubular epithelial hlwb yog ze ze rau albuminuria, uas nyob rau hauv lem activates lub unfolded protein teb [77] induce apoptosis [78]. Qhov inhibition ntawm apoptosis tuaj yeem ua rau autophagy hauv tubular epithelial hlwb [79], ua rau mob hnyav dua thiab fibrosis [80,81]. Hyperglycemia tseem tuaj yeem ua rau lub raum tubular epithelial hlwb poob lawv cov polarity thiab tau txais kev tsiv teb tsaws thiab cuam tshuam [82], ua rau muaj kev nthuav tawm ntawm fibronectin thiab -smooth leeg actin (-SMA) thiab txo qis ntawm E-cadherin ua rau fibrosis.
3.4. Endothelial Cell Dysfunction hauv Diabetes-Renal Fibrosis
Fibrosis yog yam ntxwv ntawm cov kab mob raum mob ntev ntawm ib qho etiology thiab nws thiaj li ua rau lub raum tsis ua haujlwm (Daim duab 2). Tsis ntev los no, ob peb lub cim tshiab tshiab uas tswj lub raum fibrosis tau tshaj tawm. Glucocorticoid receptor (GR) yog ib qho tshuaj tiv thaiv kab mob hauv lub cev uas kho cov tshuaj steroid hormones thiab feem ntau nthuav tawm hauv ntau hom cell, suav nrog raum. Lub luag haujlwm ntawm glucocorticoids hauv cov kab mob plawv thiab lub raum yog qhov nyuaj. Endothelial GR yog tus tswj tsis zoo ntawm vascular o hauv cov qauv ntawm sepsis thiab atherosclerosis [83,84]. Kev poob ntawm endothelial GR tuaj yeem ua rau muaj kev cuam tshuam ntawm Wnt signaling txoj hauv kev, uas ua rau lub raum fibrosis [85]. Yog li, endothelial GR yog ib qho tseem ceeb antifibrotic molecule hauv ntshav qab zib.
Daim duab 2. Endothelial cell dysfunction nyob rau hauv lub raum fibrosis. AcSDKP: N-acetyl-seryl-aspartyl-proline; ECM: extracellular matrix; EndMT: kev hloov pauv endothelial-rau-mesenchymal; FGFR: fibroblast kev loj hlob zoo receptor; GR: glucocorticoid receptor; GRE: glucocorticoid cov ntsiab lus teb; TGF-: transforming kev loj hlob factor-; MAP4K4: mitogen-activated protein kinase kinase kinase kinase 4. Liab SIRT3 qhia tsis txaus thiab dub SIRT3 qhia tias txaus. ↑: nce qib ntawm kev qhia; ↓: Txo qis hauv qib qhia.
Transgenic nas nrog txo STAT3 ua kom muaj peev xwm ua kom pom cov proteinuria tsawg, mesangial expansion, cell proliferation, macrophage infiltration, o, thiab txawv txav matrix synthesis thaum kho nrog streptozotocin rau ntshav qab zib [86]. Mitochondrial SIRT3 yog ib qho NAD ntxiv -dependent deacetylase, uas feem ntau siv cov tshuaj antioxidant los tiv thaiv cov kab mob kev laus [87]. SIRT3 deficiency tuaj yeem ua rau muaj qhov tsis zoo ntawm cov tshuaj insulin, lub raum fibrosis, nce mitochondrial protein acetylation, thiab nce mitochondrial oxidative stress [88]. SIRT1 siv cellular NAD ntxiv rau deacetylate ntau yam proteins koom nrog hauv mitochondrial biogenesis, oxidative stress, inflammatory apoptosis, thiab autophagy. Inhibition ntawm acetylation-NF-κB los ntawm kev ua kom SIRT1 txhim kho raum mob hauv cov nas mob ntshav qab zib [89].
Nyob rau hauv cov xwm txheej hyperglycemic, kev txo qis ntawm AMPK/SIRT1/PGC-1 induces hypertrophy, ROS, thiab mitochondrial thiab autophagy dysfunction, tag nrho cov uas txhawb txoj kev loj hlob ntawm DKD. AMPK upregulates SIRT1 los ntawm kev nce cellular NAD ntxiv rau qib [90], thiab ob qho tib si AMPK thiab SIRT1 tau raug txheeb xyuas tias yog intracellular zog sensors, uas, ntsig txog, ntes thiab teb rau AMP / ATP thiab NAD ntxiv / NADH piv, thiab tau qhib los ntawm kev siv hluav taws xob. tej yam kev mob thiab inactivated nyob rau hauv DM [91].
Nws kuj tseem paub tias FGF (fibroblast kev loj hlob yam tseem ceeb) kev taw qhia tswj kev ua haujlwm ntawm endothelial barrier thiab endothelial cell ciaj sia los ntawm kev khi nrog FGFR [92]. Lub AcSDKP-FGFR1-MAP4K4 axis muaj lub luag haujlwm tseem ceeb hauv kev sib ntaus sib tua EndMT-koom nrog cov kab mob fibrotic [93] thiab, raws li lub hom phiaj ntawm AcSDKP, endothelial FGFR1 yog qhov tseem ceeb raws li cov tshuaj tua kab mob core molecule [94].
4. Kev cai hloov pauv txawv txav ua rau DKD
Kev tswj hwm kev hloov pauv yog qhov tseem ceeb rau kev saib xyuas ntawm cellular homeostasis. Txawm li cas los xij, hyperglycemia paub tias yog transcriptionally induce qhov kev qhia ntawm cov noob caj noob ces, uas tau los ua constitutively qhia txawm tias tom qab hyperglycemia raug tswj, thiab qhov no tuaj yeem ua rau lub raum puas hauv cov neeg mob DKD [95]. Nqe lus no piav qhia txog kev tswj hwm kev hloov pauv li cas cuam tshuam rau DKD.
4.1. Dysregulation of Transcription Factors thiab DKD
Cov kev hloov pauv tau khi rau cov kab ke tshwj xeeb hauv cov neeg txhawb nqa los tswj cov kev hloov pauv, thiab, nyob rau hauv cov ntshav qabzib siab, ntau txoj hauv kev hloov pauv cov teeb liab tau qhib los tswj cov ntawv sau, uas tuaj yeem cuam tshuam rau kev txhim kho ntawm DKD. Nws paub zoo tias Wnt signaling tseem cuam tshuam rau hauv podocyte fibrosis [96]; Piv txwv li, cov piam thaj siab tau paub los ua kom Wnt teeb liab hloov txoj hauv kev, ua rau phosphorylation ntawm -catenin. Phosphorylated -catenin tom qab ntawd qhib cov ntaub ntawv ntawm Snail1, MMP-7, thiab Fsp1, thiab txhawb nqa podocyte dedifferentiation thiab mesenchymal transformation ua rau podocyte fibrosis [97]. Caudal-hom homeobox transcription factor 2 (CDX2) tuaj yeem qhib qhov kev hloov pauv thiab kev qhia ntawm cystic fibrosis transmembrane conductance regulator (CFTR) txhawm rau txhawm rau Wnt signaling thiab tiv thaiv fibrosis [98], thiab ib qho kev tshawb fawb thaum ntxov qhia tau hais tias CDX2 txhim kho lub raum tubular qhov txhab hauv DKD cov neeg mob thiab tus nas DKD qauv [98].
ROS plays lub luag haujlwm tseem ceeb hauv tubulointerstitial fibrosis tshwm sim los ntawm kev ua kom myofibroblasts [99]. Ib qho tshuaj tiv thaiv oxidative transcription, NF-E2- ntsig txog yam 2 (NRF2), paub tias ua kom cov ntaub ntawv hloov pauv ntawm glutathione peroxidase 2 (GPX2) kom nce oxidative kev nyuaj siab, mob, thiab apoptosis, ua rau raug mob mus tas li nrog raum fibrosis. thiab DKD [100]. NRF2 qhia tau hais tias tsim nyog; Txawm li cas los xij, nws yog degraded los ntawm NRF2- Kelch-zoo li ECH-koom nrog protein 1 (Keap1) ntawm txoj kev ubiquitin-proteasome [101]. Raws li Keap1 muaj cov cysteine reactive residues uas tuaj yeem tsim adducts nrog oxidants thiab electrophiles kom hnov txog cellular oxidative kev nyuaj siab, NRF2 yog stabilized nyob rau hauv oxidative kev nyuaj siab. NRF2 ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv lub raum hlwb los ntawm kev raug mob oxidative los ntawm kev ua kom cov noob encoding glutathione thiab NADPH los tawm tsam oxidative kev nyuaj siab [102], thiab tuaj yeem txuas ntxiv rau txoj kev pentose phosphate los ntawm kev tsim cov NADPH, uas yuav cuam tshuam nrog kev tiv thaiv ntawm oxidative. kev puas tsuaj [102].
FoxO1 yog lwm qhov kev hloov pauv uas cuam tshuam nrog DKD. Ntau cov noob tswj hwm los ntawm FoxO1 paub tias tiv thaiv lub raum tubulointerstitial fibrosis thiab apoptosis, ob qho tib si ua lub luag haujlwm tseem ceeb hauv kev tsim cov kab mob ntawm DKD [103]. Nws paub tias cov piam thaj siab txhawb nqa FoxO1 phosphorylation hauv ob lub raum [104] los qhib cov kev hloov pauv ntawm cov noob koom nrog hauv gluconeogenesis thiab glycogenolysis, yog li ua rau muaj proteinuria thiab lub raum fibrosis [105]. Inhibition ntawm kev ua haujlwm ntawm FoxO1 los ntawm cov khoom siv ntuj tsim los yog cov tshuaj hluavtaws tau pom tias ua rau lub raum cell puas nyob rau hauv ib puag ncig siab-qabzib [106]. Dachshund homolog 1 (DACH1) yog lwm qhov kev hloov pauv uas cuam tshuam nrog DKD. DACH1 recruits Pax transactivation-domain interacting protein (PTIP) rau repress transcription hauv podocytes; qhov no yuav tsum tau DACH1 ib ntus tshwj xeeb DNA khi thiab txo cov methylation ntawm histone H3 ntawm K4 kom qhib cov ntaub ntawv ntawm NELL2 thiab ua rau muaj kev raug mob podocyte [107].
4.2. Kev cuam tshuam ntawm Genes Regulated los ntawm Krϋppel-Like Factors hauv DKD
Krϋppel-zoo li yam (KLFs) yog ib pab pawg ntawm cov ntsiab lus hloov pauv uas suav nrog tsawg kawg 27 cov proteins. Ntau ntawm KLF cov tswv cuab, suav nrog KLF2, KLF4, KLF5, KLF6, thiab KLF15, paub tias yuav ua kom cov noob hauv glomerular endothelial hlwb lossis podocytes los tiv thaiv fibrosis; Txawm hais tias KLF 10 zoo li muaj kev cuam tshuam rau lub raum [108–115]. Kev koom tes ntawm KLFs hauv DKD yog cov ncauj lus kom ntxaws hauv cov kab hauv qab no.
4.2.1. Renoprotective nyhuv ntawm KLFs
KLF2 ua kom muaj kev phom sij, occludin, txhawm rau tiv thaiv qhov kev tsim ntawm cov hlwb ntawm cov hlab endothelial thiab tswj kev ncaj ncees ntawm qhov thaiv Endothelial [116]. Nyob rau hauv cov ntshav qabzib siab, qhov kev qhia ntawm KLF2 raug txwv los ntawm FoxO1 [117], uas ua rau glomerular endothelial cell thiab podocyte puas [113].
KLF4 qhia txo GpC methylation ntawm nephrin txhawb nqa thiab cov neeg txhawb nqa ntawm lwm cov cim epithelial [111] los tiv thaiv ob lub raum nyob rau hauv ib txwm muaj, tab sis qib qabzib siab tau pom tias txo qis KLF4 tus tub txib RNA qib thiab nce kev qhia ntawm macrophage migration inhibitory yam ( MIF) thiab MCP-1, nyob rau hauv tus txheej txheem kho los ntawm TGF- 1 thiab feem ntau raug txwv los ntawm KLF4 [118]. TGF- 1 yog tus tsav tsheb tseem ceeb ntawm lub raum fibrosis, thiab kev qhia ntawm TGF- 1 txhawb txoj kev loj hlob thiab kev loj hlob ntawm lub raum kab mob [119] thaum tseem ua kom cov lus qhia ntawm Twist1 lossis Snail kom ntev G2 / M ntes. thiab txhawb lub raum fibrosis [120] KLF-4 ua los txwv cov cell proliferation thiab sib txawv induced los ntawm TGF{14}} [121].
Tsis tas li ntawd, KLF5 cuam tshuam qhov kev qhia ntawm Bax, caspase-3, caspase-8, thiab caspase-9 hauv podocytes [122] los ntawm kev thaiv kev ua kom cov mitogen-activated protein kinase (MAPK) txoj kev [122,123]. Ib txoj kev tshawb fawb dhau los tau lees paub tias kev tswj hwm P38-induced apoptosis [124] thiab inhibiting apoptosis ntawm MAPK txoj hauv kev tuaj yeem yog lub tswv yim zoo los txo lub raum fibrosis [125].
Cytochrome c-oxidase (COX) plays lub luag haujlwm tseem ceeb hauv kev tswj hwm lub zog aerobic los ntawm mitochondrial respiratory saw. Hauv podocytes, KLF6 tswj kev ua haujlwm mitochondrial los ntawm COX sib dhos noob (SCO2), uas hloov qhov sib npaug ntawm mitochondrial ua pa thiab glycolytic txoj hauv kev los tiv thaiv mitochondrial dysfunction thiab podocyte apoptosis [109]. Tsis tas li ntawd, KLF15 inhibits TGF- 1 los ntawm ERK/MAPK thiab JNK/MAPK txoj hauv kev [126] thiab yog tus tswj xyuas qhov tseem ceeb ntawm kev sib txawv ntawm podocyte thiab tiv thaiv kev puas tsuaj ntawm podocyte [127].
4.2.2. KLF10 Ua rau raum puas hauv DKD
KLF10 muaj ntau lub luag haujlwm hauv podocyte tsis ua haujlwm thiab raug mob. TGF- 1, pob txha morphogenetic protein-2 (BMP-2), thiab epidermal growth factor (EGF) induction ntawm KLF10 qhia ua lub luag haujlwm tseem ceeb hauv kev sau cov noob xws li Smad, uas yog koom nrog hauv cell proliferation, apoptosis, thiab sib txawv [128]. KLF10 kuj inhibits nephrin qhia los ntawm kev sib cuam tshuam nrog DNA methyltransferase 1 (DNMT1) rau methylate nephrin promoter [115] (Daim duab 3).
Tsis tas li ntawd, KLF10 txwv tsis pub hloov pauv ntawm ntau cov noob tshwj xeeb qhia hauv podocytes, suav nrog cov encoding Wilms 'cov qog 1 protein (WT1), podocin, synaptophysin, thiab nephrin, thaum kawg ua kom cov lus qhia ntawm lysine-specific demethylase (KDM6A), uas yog qhov tseem ceeb. mus rau kev saib xyuas ntawm lub raum ua haujlwm raws li tus tswj hwm ntawm podocyte sib txawv [129], los txhawb lub ntiaj teb epigenetic reprogramming thiab ua rau lub cev tsis meej pem [115]. Thaum kawg, KLF10-vim hais tawm ntawm KDM6A induces proteinuria thiab irreversible raum puas nyob rau hauv cov mob ntshav qab zib [115].
Daim duab 3. Hyperglycemia-induced nephrin modification induces glomerulosclerosis. Ac: acetylation; Dnmt1: DNA methyltransferase 1; EndMT: kev hloov pauv endothelial-rau-mesenchymal; HDAC4: histone deacetylase 4; IL-1 : Interleukin-1 ; KDM6A: lysine-specific demethylase; KLF 10: Krϋppel-like factor 10; Kuv: methylation; TGF-: Kev hloov pauv loj hlob; ub: ubiquitination; WT1: Wilms' qog 1 protein. ↑: nce qib ntawm kev qhia; ↓: Txo qis hauv qib qhia.
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