Pathogenesis ntawm Diabetic raum Kab Mob

Mob raum mob ntshav qab zib mellitus (DKD) yog ib qho teeb meem ntawm cov neeg mob ntshav qab zib. Nws yog hais txog cov kab mob raum ntev (DKD) uas tshwm sim los ntawm ntshav qab zib, tshwm sim los ntawm cov zis muaj protein ntau (urinary albumin-to-creatinine ratio Ntau dua lossis sib npaug li 30 mg / g) thiab (lossis) kwv yees glomerular filtration rate (eGFR)<60ml. min ¯¹. (1.73m²)¯¹ and lasted for more than 3 months, while excluding other etiologies of CKD and making a clinical diagnosis.

Nyem rau cistanche herba rau mob raum

DKD tuaj yeem ua rau lub raum puas tsuaj ntau yam. Lub raum cov hlab ntsha, glomeruli, thiab lub raum tubules txhua tus tuaj yeem koom nrog hauv kev loj hlob ntawm tus kab mob. Lub pathogenesis yog complex, thiab lub meej mechanism tseem tsis tau paub meej. Cov yam ntxwv ntawm caj ces, cov teebmeem hemodynamic, inflammatory teb, metabolic ntshawv siab, oxidative kev nyuaj siab, glomerular pathological hloov, thiab cell puas yuav muaj feem xyuam rau lub pathogenesis ntawm DKD. Kev tshawb fawb ntxiv ntawm cov kab mob ntawm DKD yog qhov tseem ceeb rau kev kho mob ntawm DKD.

Lub pathogenesis ntawm DKD yog qhov nyuaj heev thiab yog qhov tshwm sim ntawm kev sib cuam tshuam ntawm cov noob caj noob ces, epigenetics, thiab kev sib raug zoo uas tsim los ntawm kev coj cwj pwm nyuaj thiab ib puag ncig.

(1) Cov kab mob metabolic, qhov txawv txav ntawm lub raum hemodynamics, ua kom lub renin-angiotensin-aldosterone system (RAAS), oxidative kev nyuaj siab, thiab o yog txhua yam cuam tshuam rau qhov tshwm sim thiab kev loj hlob ntawm DKD. Kev sib xyaw ua ke ntawm cov yam ntxwv saum toj no ua rau muaj kev puas tsuaj rau glomerular podocytes thiab endothelial hlwb, ua rau kev nthuav dav ntawm mesangial matrix thiab thickening ntawm glomerular hauv qab daim nyias nyias, atherosclerosis, tubular atrophy, thiab fibrosis, uas tuaj yeem soj ntsuam kev kho mob proteinuria thiab / lossis txo qis. glomerular filtration rate (GFR).

1) Cov teebmeem Hemodynamic. Cov teebmeem Hemodynamic ua lub luag haujlwm tseem ceeb hauv kev txhim kho DKD. Hyperglycemia ua rau cov piam thaj ntau dhau los ntawm glomerular filtration barrier, uas ua rau cov piam thaj ntau dhau los ntawm cov tubules ze ze. Kev nthuav qhia ntau ntxiv ntawm cov piam thaj thauj khoom thiab nce loj hauv kev thauj mus los ntawm lub zog ntawm cov txheej txheem hauv cov tubular sib txuas ua ke los txhawb kev rov qab nqus cov piam thaj ntau dhau, kev hloov pauv uas ua rau cov pa oxygen xav tau ntawm lub raum cortex thiab medulla, ua rau lub raum txheeb ze ischemia thiab nce kev qhia ntawm cellular stress markers xws li neutrophil gelatinase-associated lipocalin thiab lub raum raug mob molecule 1. nce loading ntawm proximal tubules ua rau hypertrophy thiab elongation ntawm proximal tubules, thiab hypertrophy ntawm lub raum. Sodium-glucose cotransporter 2 nyob rau hauv lub tubule proximal thauj ntau ntau ntawm sodium thaum reabsorbing qabzib, ua rau txo qis sodium chloride concentration nyob rau hauv lub distal tubule thiab nyob rau hauv lub macula densa, uas yog tom qab hnov ​​los ntawm macula densa nrog txo sodium ion concentrations Dilate. Lub afferent arteriole los ntawm kev tawm tswv yim ntawm lub teeb, induce lub granule hlwb kom secrete renin, thiab tsim angiotensin II los ntawm kev ua kom nquag plias ntawm tsev neeg angiotensin, thiab xaiv cog lus rau efferent arteriole. Cov teebmeem hemodynamic saum toj no ua rau GFR nce ntxiv. Siab, ua rau glomerular ultrafiltration thiab glomerular hypertension. Nrog rau kev txhim kho ntawm glomerular hypertrophy, glomerular siab poob qis, tab sis glomerular ultrafiltration tseem pheej. Hauv kev kho mob, kev tswj hwm kev kub siab tseem ceeb heev rau kev kho mob ntawm DKD. Raws li ib qho ntawm cov kev pheej hmoo txaus ntshai ntawm ntshav qab zib mellitus, ntshav siab ua lub luag haujlwm tseem ceeb hauv kev txhim kho DKD, thiab kev sib nrig sib cuam tshuam ntawm ob tuaj yeem txhawb kev nce qib ntawm GFR.

2) Kev cuam tshuam ntawm cov metabolism hauv qabzib.

A. Hyperglycemia txhawb kev txhim kho ntawm txoj kev hexosamine

Glucose hauv lub cev muab lub zog rau lub cev los ntawm txoj kev glycolytic, lub voj voog tricarboxylic acid, thiab ATP tsim los ntawm oxidative phosphorylation. Nyob rau hauv lub xeev hyperglycemic, cov piam thaj oxidation txoj hauv kev cuam tshuam hauv cov hlwb endothelial, mesangial hlwb, thiab podocytes, tso cai rau hloov cov piam thaj mus rau lwm cov biofuels xws li fatty acids thiab ketones thiab ua rau cellular puas. Nyob rau tib lub sijhawm, txoj hauv kev glycolytic, qabzib aerobic thiab anaerobic metabolism, tau nce hauv cov tubule ze ze, thiab txoj hauv kev hexosamine, uas fructose{0}}phosphate tau hloov pauv los ntawm txoj kev glycolytic, tau nce ntxiv ntawm 6 -Glucosamine. 6-phosphate yog tsim los ntawm kev ua ntawm phosphofructoyltransferase, thiab thaum kawg hloov mus rau uracil N-acetylglucosamine diphosphate; ntawm lawv, glucosamine txo qis ATP qib hauv lub cell, yog li inhibiting cov dej ntws ntawm cov tshuaj insulin hloov pauv txoj hauv kev Phosphorylation ntawm lub hom phiaj yog qhib, yog li inhibiting insulin cuam tshuam thiab exacerbating metabolic ntshawv siab.

B. Hyperglycemia ua rau kev txhim kho polyol

Txoj kev polyol yog catalyzed los ntawm aldose reductase thiab sorbitol dehydrogenase, thiab aldose reductase yog tus nqi txwv enzyme ntawm txoj kev no. Aldose reductase txo cov piam thaj rau sorbitol thaum lub sijhawm hloov pauv ntawm nicotinamide adenine dinucleotide phosphate (NADPH) txo qis rau nicotinamide adenine dinucleotide phosphate. Feem ntau, aldose reductase muaj qhov tsis sib haum xeeb rau cov piam thaj thiab txoj hauv kev polyol yog nyob rau hauv lub xeev uas tsis tshua muaj metabolic. Nyob rau hauv cov xwm txheej hyperglycemic, affinity ntawm aldose reductase rau cov piam thaj nce, thiab txoj hauv kev polyol tau qhib thiab metabolized los tsim cov sorbitol ntau. Vim qhov tsis zoo permeability ntawm lub raum hlwb rau sorbitol, nws cov khoom oxidized fructose tsis yooj yim metabolized, ua rau muaj kev nce siab hauv cov cellular osmotic siab, uas nws thiaj li ua rau edema thiab kev puas tsuaj rau lub raum hlwb thiab cuam tshuam rau lub cev kev ua haujlwm, yog li ua rau lub raum puas tsuaj ntxiv. .

C. Hyperglycemia ua rau muaj kev nce ntxiv hauv cov khoom lag luam glycation kawg

AGEs are the end products of non-enzymatic catalytic reactions between proteins, fats, nucleic acids, and reducing sugars in the state of high glucose in the body, which can promote the release of transforming growth factor-β, stimulate the synthesis of collagen matrix components, and lead to GBM thickening, thereby It affects the function of the filtration membrane, eventually leading to the progressive change of GFR and the loss of glomerular function. Furthermore, the interaction of AGEs with their receptors plays an important role in the pathogenesis of DKD. AGEs receptor is a multi-ligand receptor widely present in smooth muscle cells, macrophages, endothelial cells, and astrocytes. During hyperglycemia, AGEs bind to AGEs receptors on macrophages, resulting in oxidative stress response and nuclear factor-κB (nuclear factor-κB, NF-κB) activation, and NF-κB regulates interleukin (interleukin, IL)-1α, The release of cytokines such as IL-6 and tumor necrosis factor-α activates the inflammatory response, which in turn exacerbates renal cell damage. In addition, NF-κB can also promote the expression and release of endothelin 1 and vascular endothelial growth factor. These cytokines can mediate the injury of vascular endothelial cells and the apoptosis of tissue cells, thereby aggravating the damage to glomerular function. A study of long-term diabetic patients (duration >50 xyoo) pom tias cov neeg mob uas tsis yog DKD muaj glomerular pyruvate kinase ntau dua li cov neeg mob DKD, qhia tias kev tswj cov piam thaj oxidation yog qhov tseem ceeb rau kev tiv thaiv podocyte thiab glomerular puas.

3) Cov lipid metabolism tsis zoo yog koom nrog kev txhim kho DKD

lipid metabolism tsis zoo tuaj yeem koom nrog hauv kev txhim kho DKD los ntawm ntau txoj hauv kev. Lub raum lipid tsub zuj zuj thiab fatty acid oxidation hloov pauv hauv cov neeg mob ntshav qab zib yog qhov tseem ceeb txuas hauv kev loj hlob ntawm DKD. Hyperlipidemia tsub kom cov fatty acid cov ntsiab lus ntawm albumin, thiab albumin-bound long-chain saturated fatty acids tuaj yeem ua lub luag haujlwm tseem ceeb hauv lub raum tubular puas. Lub raum tubular epithelial hlwb coj mus ntev-chain fatty acids los ntawm CD36 transporter, thiab kev qhia ntawm CD36 nyob rau hauv cov neeg mob ntshav qab zib yog li tswj, uas ntxiv aggravates lub tsub zuj zuj ntawm fatty acids. Cov fatty acids accumulated induce apoptosis ntawm lub raum tubular epithelial hlwb los ntawm activating p38 mitogen-activated protein kinase txoj kev. Tsis tas li ntawd, nws tau pom tias qhov nce ntawm qhov tsis-esterified fatty acids khi rau albumin ua rau mitochondrial dysfunction thiab superoxide ntau lawm, thaum kawg inducing apoptosis nyob rau hauv lub raum tubular epithelial hlwb. Ntxiv nrog rau qhov nce fatty acid uptake, nce lipid synthesis nyob rau hauv lub raum kuj yog ib qho tseem ceeb ua rau lipid tsub zuj zuj. Sterol-regulatory element binding proteins (SREBPs) yog lub luag haujlwm rau kev tswj cov roj cholesterol synthesis, uptake, thiab fatty acid biosynthesis. Mammalian SREBPs yog co-encoded los ntawm sterol regulatory element-binding transcription factor-1 thiab sterol regulatory element-binding transcription factor-2. Kev qhia ntawm SREBP1 tus tub txib RNA tau nce siab thaum lub sijhawm hyperglycemia, thiab qib ntawm triacylglycerol hauv lub raum tau nce ntxiv, uas ua rau muaj kev cuam tshuam ntawm lipid metabolism thiab lipid tsub zuj zuj hauv ob lub raum. Glomerular lipid deposition tseem tuaj yeem ua rau muaj kev sib txuam ntawm extracellular matrix (ECM), uas nws thiaj li ua rau glomerulosclerosis thiab ua rau lub raum tsis ua haujlwm.

4) Inflammatory teb. DKD feem ntau suav hais tias yog kab mob inflammatory teb, thiab theem ntawm o nce nrog kev loj hlob ntawm tus kab mob, nws thiaj li ua rau glomerulosclerosis. Cov kev tshawb fawb tau pom tias cov cim rau lub raum muaj feem cuam tshuam nrog proteinuria, ECM deposition, thiab nce zuj zus hauv GFR. Nyob rau theem pib ntawm DKD, ntau cov leukocytes sib sau ua ke hauv glomerulus thiab tubulointerstitium, thiab infiltration ntawm cov hlwb inflammatory thiab tso tawm cov inflammatory yam tseem ceeb ua lub luag haujlwm tseem ceeb hauv kev txhim kho DKD. Kev ua kom muaj zog thiab txhawb nqa kev nthuav tawm ntawm cov noob caj ces thiab txoj hauv kev ua kom lub luag haujlwm tseem ceeb hauv kev txhim kho DKD. Vim yog cov ntaub so ntswg puas, ntau cov hlwb inflammatory sib sau ua ke hauv lub raum cov ntaub so ntswg, thiab ntau cov hlwb inflammatory thiab lawv cov khoom [xws li cytokines, chemokines, activated complement, thiab reactive oxygen hom (reactive oxygen hom, ROS)] induce. kev tsim khoom ntawm DKD. Nyob rau hauv lub xub ntiag ntawm glomerular ultrafiltration thiab lub raum fibrosis, knockout ntawm Rag1 tsis ua rau cov ntshav qab zib-kua proteinuria. Tsis tas li ntawd, chemokine receptor inhibitors txo cov proteinuria hauv cov neeg mob ntshav qab zib hom 2 thiab mob raum mob. Cov qib ntawm tsub zuj zuj ntawm inflammatory cells nyob rau hauv ob lub raum ntawm cov kab mob ntshav qab zib nas qauv yog ze ze rau qhov poob ntawm lub raum ua hauj lwm, thiab inhibiting lub recruitment ntawm inflammatory cells yuav txo tau lub raum puas. Nws tuaj yeem pom tau tias inhibiting kev sib sau ntawm lub raum inflammatory cells tuaj yeem tiv thaiv kev tsim cov proteinuria thiab txo cov raum puas. Cov kab mob ua paug ua lub luag haujlwm tseem ceeb hauv kev txhim kho DKD. Hauv DKD, kev qhia ntawm cytokines xws li chemokine 5, IL-6, qog necrosis factor-, thiab monocyte chemoattractant-1 tau nce. Qhov loj heev tso tawm ntawm IL-6 thiab qog necrosis factor- txhim kho lub zos inflammatory teb ntawm lub raum, txhawb lub proliferation ntawm mesangial hlwb, accelerate lub deposition ntawm ECM, thiab aggravated lub raum raug mob. Knockout los yog inhibition ntawm monocyte chemoattractant-1 tuaj yeem ncua kev loj hlob ntawm DKD. Kev ua kom NF-κB thiab Janus kinase-cim transducer thiab activator ntawm transcription signal transduction txoj kev yog tus yuam sij rau cytokine ntau lawm, ob qho tib si uas yuav ua kom cov txheej txheem ntawm DKD los ntawm kev tswj cov kev qhia ntawm stimulating adhesion molecules thiab pro-inflammatory yam.

5) oxidative kev nyuaj siab. Hyperglycemia tuaj yeem ua rau muaj cov tshuaj lom neeg nruab nrab, thiab ROS yog ib qho tseem ceeb tshaj plaws intermediates. ROS ua lub luag haujlwm tseem ceeb hauv cov txheej txheem physiological ntawm kev loj hlob, kev sib txawv, apoptosis, thiab kev tiv thaiv kab mob ntawm ntau lub hlwb. Kev sib sau ntawm ROS thiab tiam ntawm superoxide yog qhov tseem ceeb ua rau DKD hauv hyperglycemia, uas tuaj yeem ua rau ESRD yooj yim. Xanthine oxidase, cytochrome P450, uncoupled endothelial nitric oxide synthase, mitochondrial respiratory saw, thiab NADPH oxidase txhua tus ua lub luag haujlwm tseem ceeb hauv ROS synthesis, ntawm cov mitochondrial dysfunction thiab NADPH oxidase yog qhov tseem ceeb tshaj plaws. Nyob rau hauv cov xwm txheej ntawm lub cev, xanthine oxidase hauv lub raum tuaj yeem tsim ROS uas tsis tuaj yeem kuaj pom los ntawm txoj kev purine metabolic. Kev tshawb fawb los ntawm Eid et al. tau pom tias cytochrome P450 (tshwj xeeb tshaj yog cytochrome 4A) tuaj yeem ua rau cov khoom tsim ROS los ntawm kev ua kom NADPH oxidase, ua rau lub raum cell puas thiab tuag rau cov nas mob ntshav qab zib. Uncoupled endothelial nitric oxide synthase tuaj yeem txhawb kev tsim ntawm ROS thiab ua rau txo qis ntawm nitric oxide nyob rau hauv endothelial hlwb, thaum tsub zuj zuj ntawm nitric oxide tuaj yeem ua rau endothelial cell dysfunction thiab ua puas lub filtration membrane muaj nuj nqi. Tsis tas li ntawd, oxidation ntawm mitochondrial substrates nyob rau hauv cov neeg mob ntshav qab zib yog txhim kho, lub mitochondrial membrane muaj peev xwm txhim kho, thiab electrons raug xa mus los ntawm mitochondrial electron thauj saw uas ua rau superoxide ntau lawm. Nyob rau hauv cov xwm txheej ntawm lub cev, kev ua haujlwm ntawm NADPH oxidases feem ntau yog qis, tab sis cov haujlwm ntawm NADPH oxidases tau qhib rau hauv ntshav qab zib. Txhua NADPH oxidase subtypes yog transmembrane proteins uas hloov electrons los ntawm NADPH mus rau tag nrho biomembrane thiab tom qab ntawd txo cov pa oxygen molecules rau superoxide O2-, uas ua rau ntau tshaj superoxide nyob rau hauv vivo Lub peev xwm ntawm dismutases ua rau tsub zuj zuj ntawm superoxide nyob rau hauv lub lub raum. Tsis tas li ntawd, cov lus teb ntawm lub raum hauv lub raum hauv lub xeev ntawm hyperglycemia tau ntxiv dag zog, ntau tus kab mob inflammatory raug tso tawm, thiab tiam ntawm ROS tau nce. cov mob hauv zos hauv lub raum cov ntaub so ntswg ntawm DKD cov neeg mob. Cov kev tshawb fawb tau pom tias oxidative kev nyuaj siab kuj tuaj yeem ua rau cov kab mob pancreatic, uas muaj kev cuam tshuam ntau dua rau ROS vim qhov qis ntawm superoxide dismutase hauv pancreatic-cells. ROS tuaj yeem txhawb nqa apoptosis los ntawm ncaj qha rhuav tshem DNA thiab cov protein ntawm cov islet hlwb, thiab tseem tuaj yeem siv los ua cov cim qhia molecule los koom rau hauv kev tswj hwm ntawm insulin secretion, yog li indirectly inhibiting kev ua haujlwm ntawm islet hlwb thiab ua rau ntxiv aggravation ntawm qabzib metabolism. . Tsis tas li ntawd, ROS tuaj yeem ua rau muaj kev puas tsuaj thiab apoptosis ntawm endothelial hlwb thiab podocytes nyob rau hauv ntau txoj kev, ua rau tsis ua hauj lwm, thiab cov qauv ntawm glomerular filtration membrane yog tom qab puas, uas nws thiaj li ua rau lub raum puas thiab proteinuria.

(2) Glomerular hyperfiltration muaj ntau dua hauv T1D, thiab nws cov txheej txheem pathophysiological tsis meej. Lub mechanism ntawm qhov ua tau yog speculated yuav:

(1) Ua kom cov piam thaj reabsorption los ntawm cov tubules ze ze los ntawm sodium-glucose cotransporter 2, uas ua rau muaj kev txo qis hauv NaCl concentration hauv macula densa, ua rau tsis muaj zog tubule tawm tswv yim thiab dilation ntawm afferent arterioles kom glomerulus perfusion.

(2) Kev tsim cov tshuaj angiotensin II hauv zos ua rau muaj kev cuam tshuam ntawm cov hlab ntsha efferent, thiab tag nrho cov nyhuv yog siab glomerular sab hauv siab thiab siab pom.

(3) Cov txiaj ntsig kev tshawb fawb uas twb muaj lawm tau pom tias cov caj ces tsis tuaj yeem piav qhia tag nrho cov kab mob ntawm DKD, thiab kev cuam tshuam ntawm epigenetics thiab ib puag ncig ntawm qhov tshwm sim thiab kev loj hlob ntawm DKD tau txais kev saib xyuas dav.

Mob ntshav qab zib tuaj yeem ua rau muaj kab mob microvascular, thiab DKD yog qhov tshwm sim ntau tshaj plaws thiab loj microvascular teeb meem thiab tau dhau los ua qhov tseem ceeb ntawm ESRD tshiab. Cov kab mob pathogenic thiab pathogenesis ntawm DKD yog intricate, nrog rau kev ua kom muaj ntau lub hlwb thiab ntau txoj kev taw qhia. Genetic yam, hemodynamic teebmeem, inflammatory teb, metabolic ntshawv siab, oxidative kev nyuaj siab, glomerular pathological hloov, thiab cell puas ua lub luag hauj lwm tseem ceeb nyob rau hauv lub pathogenesis ntawm DKD, thiab lawv cov teebmeem ua ke ua rau lub pathogenesis ntawm DKD. tshwm sim thiab txhim kho. Sodium-glucose cotransporter 2 yog qhov kev tshawb fawb tsom ntawm kev kho DKD hauv xyoo tas los no. Sodium-glucose cotransporter 2 inhibitors tuaj yeem txhim kho glomerular ultrafiltration thiab txo cov txheej txheem ntawm DKD. Tsis tas li ntawd, kev siv renin-angiotensin-aldosterone system blockers tuaj yeem txo qhov tshwm sim ntawm albuminuria hauv cov neeg mob ntshav siab thaum tswj cov ntshav siab, tab sis tseem tsis muaj cov tshuaj tshwj xeeb rau kev kho mob ntawm DKD, thiab cov pathogenesis ntawm DKD thiab kev kho mob. txoj kev tseem xav tau kev tshawb fawb ntxiv.