Endogenous Fructose Metabolism tuaj yeem piav qhia txog Warburg Effect Thiab Kev Tiv Thaiv Ntawm SGLT2 Inhibitors hauv Kab Mob Raum Ntev

edmund.chen@wecistanche.com

Cov kab mob qis qis qis qis hauv qab cov kab mob ntawm cov kab mob tsis sib kis, suav nrog mob ntev.kab mob raum(CKD). Kev mob plab yog ib txoj kev ua haujlwm lom neeg nrog rau kev hloov pauv biochemical nrog lub zog, amino acid, lipid thiab nucleotides. Tsis ntev los no, glycolysis tau pom tias yuav nce ntxiv hauv ntau yam kab mob o, suav nrog ntau hom kab mob.mob raum. Txawm li cas los xij, cov xwm txheej pib glycolysis tseem tsis meej. Ntxiv cov suab thaj uas muaj fructose muaj nyob rau hauv ze li ntawm 70 feem pua ​​​​ntawm cov zaub mov ua tiav thiab tau cuam tshuam rau hauv etiology ntawm ntau yam kab mob tsis sib kis. Hauvraum, fructose raug thauj mus rau hauv cov tubules ze ze ntawm ntau lub tsheb thauj mus los los kho cov txheej txheem pathophysiological. Fructose tuaj yeem tsim nyob rau hauvraumthaum lub sij hawm qabzib reabsorption (xws li hauv ntshav qab zib) thiab los ntawmintrarenalhypoxia uas tshwm sim hauv CKD. Fructose metabolism kuj muab biosynthetic precursors rau o los ntawm kev hloov cov intracellular metabolic profifile los ntawm mitochondrial oxidative phosphorylation rau glycolysis txawm tias muaj cov pa, uas zoo ib yam li cov nyhuv Warburg hauv kev mob qog noj ntshav. Qhov tseem ceeb, uric acid, uas yog cov khoom lag luam ntawm fructose metabolism, yuav ua lub luag haujlwm tseem ceeb hauv kev nyiam glycolysis los ntawm kev ua kom o thiab suppressing aconitase hauv lub voj voog tricarboxylic acid. Qhov sib xyaw ua ke ntawm glycolytic intermediates txuas mus rau kev tsim cov biosynthetic precursors, proteins, lipids, thiab nucleic acids, kom tau raws li qhov xav tau ntawm lub zog ntxiv rau kev mob hauv zos. Ntawm no, peb tham txog qhov ua tau ntawm fructose thiab uric acid tuaj yeem kho qhov hloov pauv hloov mus rau glycolysis hauv CKD. Peb kuj qhia tias sodium-glucose cotransporter 2 (SGLT2) inhibitors tuaj yeem ua rau qeeb ntawm CKD los ntawm kev txo qis.intrarenalqabzib, thiab tom qab ntawd qib fructose.

Ntsiab lus:fructose, Warburg nyhuv, CKD - ​​mob raum kab mob, o, fifibrosis, raum.

Taw qhiaNtevmob raum(CKD) tau nce nyob rau hauv kaum xyoo dhau los thiab yog qhov ua rau muaj mob hnyav thiab tuag taus. Central rau ob qho tib si mob ntshav qab zib thiab tsis mob ntshav qab zib CKD yogintrarenalo thiab fibrosis. Ntawm no peb nthuav tawm cov kev xav tshiab uas fructose, txawm tias muab hauv kev noj haus lossis tsim tawm endogenously, tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev ua kom muaj kab mob los ntawm nws lub peev xwm los ua kom mob plab los ntawm Warburg effect. Peb kuj pom zoo tias qhov no tuaj yeem piav qhia txog kev tiv thaiv cov txiaj ntsig ntawm sodium-glucose cotransporter-2 (SGLT2) inhibitors. Thaum lwm tus tau hais tias SGLT2 inhibitors tuaj yeem muablub raumkev tiv thaiv los ntawm kev thim rov qab cov nyhuv Warburg (1), ntawm no peb xav kom endogenous fructose metabolism tuaj yeem yog tus neeg nruab nrab ntawm Warburg cov nyhuv hauv cov ntawv sau no thiab peb xav kom muaj lub tswv yim los ntawm SGLT2 inhibitors tuaj yeem txo cov fructose metabolism hauv.raum.Txij li thaum fructose yog endogenously tsim txawm nyob rau hauv cov mob uas tsis yog mob ntshav qab zib, peb lub tswv yim yuav siv tau rau yuav ua li cas SGLT2 inhibitors txhim kho cov ntshav qab zib thiab tsis yog mob ntshav qab zib CKD.

FRUCTOSE, METABOLIC SYNDROME, thiab CKDFructose yog cov suab thaj yooj yim tam sim no hauv cov txiv hmab txiv ntoo thiab zib ntab, thiab tseem yog ib feem tseem ceeb ntawm cov suab thaj ntxiv xws li sucrose (ib qho disaccharide ntawm fructose thiab qabzib) thiab siab fructose pob kws phoov (HFCS, kev sib xyaw ntawm monosaccharide ntawm fructose thiab qabzib). Kev noj qab haus huv ntawm fructose tau nce siab nyob rau xyoo pua dhau los hauv kev koom tes nrog tag nrho kev noj cov suab thaj ntxiv. Fructose kuj tuaj yeem tsim tawm hauv lub cev los ntawm kev ua kom cov aldose reductase (AR) hauv txoj kev polyol (Daim duab 1). Ntau yam stimuli paub tias yuav ua rau AR qhia ntau ntxiv, suav nrog ischemia, hypoxia, hyperglycemia, hyperosmolality, thiab uric acid (2-5). Thaum endogenous fructose ntau lawm feem ntau yog tsawg, muaj ntau cov pov thawj tias endogenous fructose ntau lawm tsis yog nyob rau hauv cov ntshav qab zib (6, 7), tab sis kuj los ntawm cov khoom noj carbohydrate siab, khoom noj qab zib, thiab cawv ntau rau sab hnub poob noj (8-11). ).

Kev tshawb fawb tau cuam tshuam txog lub luag haujlwm rau fructose hauv ntau yam kab mob tsis sib kis, suav nrog kev rog rog, ntshav qab zib, kab mob uas tsis yog-coholic fatty siab, thiab kab mob plawv (12, 13) thiab mob hnyav thiab mob ntev.mob raum(5, 6, 14, 15). Classically, qhov no tau raug sau tseg rau fructose cov nyhuv los txhawb oxidative kev nyuaj siab, endothelial tsis ua hauj lwm, stimulation ntawm vasopressin, thiab uric acid tiam (12, 13, 16).

Tsis ntev los no peb tau tshuaj xyuas cov pov thawj tias fructose kuj tseem tuaj yeem pab kho mob qog noj ntshav los ntawm kev hloov pauv metabolic nyiam mitochondrial ua pa dhau glycolysis, zoo li cov nyhuv Warburg (17, 18). Cov nyhuv Warburg kuj tseem yuav muaj feem cuam tshuam rau kev loj hlob ntawm cov qog nqaij hlav tsis zoo, suav nrog kev mob ntsws ntsws, kab mob plawv, mob neuronal, thiabkab mob raum(19). Ntawm no peb qhia tias cov nyhuv Warburg vim fructose tuaj yeem muaj lub luag haujlwm ntevmob raum(CKD).

FRUCTOSE METABOLISM thiab WARBURG cuam tshuamGlycolysis yog txoj kev metabolic uas hloov cov piam thaj rau hauv pyruvate, uas tuaj yeem nkag mus rau lub voj voog tricarboxylic acid (TCA) hauv mitochondria qhov twg ATP yog tsim los ntawm oxidative phosphorylation. Fructose yog txawv ntawm qabzib nyob rau hauv uas nws yog tshwj xeeb metabolized rau Fructose 1-phosphate (Fru1P). Fru1P tuaj yeem raug metabolized tom qab txuas nrog txoj kev glycolytic (Daim duab 1). Thaum lub sij hawm fructose metabolism, qhov ua kom C isoform offructokinase (Ketohexokinase-C; KHK-C) txo ob qho tib si phosphate thiab adenosine triphosphate (ATP) hauv cell, thiab ua rau degradation ntawm adenosine monophosphate (AMP) los ntawm AMP deaminase ntau lawm rau uric acid. . Uric acid yog ib qho intracellular pro-oxidant thiab muaj peev xwm ntawm suppressing aconitase, lub enzyme catalyzing citrate rau isocitrate nyob rau hauv lub voj voog TCA. Raws li qhov tshwm sim, fructose tuaj yeem ua raws li kev hloov pauv hauv metabolic nyiam lub zog sai dua los ntawm glycolysis piv rau lub zog tsim los ntawm mitochondrial ua pa txawm tias muaj cov pa oxygen. Zoo ib yam li Warburg cov nyhuv hauv kev loj hlob ntawm qog nqaij hlav, activated glycolysis muab ob peb intermediates txuas mus rau tom ntej metabolic txoj kev, xws li pentose phosphate txoj kev, hexosamine txoj kev, thiab lipid synthesis, thiab cov biosynthetic precursors pab rau inflammatory cov tshuaj tiv thaiv (17).

MECHANISS los ntawm qhov twg FRUCTOSE stimulates raum mob plabHauvraum, kev noj haus fructose yog filtered kiag li los ntawm glomerulus, thiab reabsorbed nyob rau hauv lub proximal tubular epithelial hlwb los ntawm fructose transporters qhia nyob rau hauv lub apical membrane. Lub fructose yog physiologically siv nyob rau hauv lub cytosol raws li ib tug substrate rau gluconeogenesis kom tswj systemic qabzib concentration (18). CovraumNws muaj peev xwm tsim fructose endogenously los tiv thaiv ntau yam kab mob pathological. Piv txwv li, ischemia, siab qabzib, thiab siab osmolarity, tag nrho cov no yog cov khoom tseem ceeb ntawm CKD, txhawb nqa aldose reductase thiab activates txoj kev polyol (Daim duab 2).

Kev noj zaub mov ntau dhau ntawm fructose yog tshem tawmraum. Qhov tseeb, cov nas ib txwm tsim mob me me tubulointerstitial o thiab fifibrosis ntawm cov khoom noj fructose siab. Tubular epithelial vimmentin qhia, collagen III deposition, thiab lub cev tsis muaj zog ntawm tes tau raug ntxias los ntawm kev noj haus fructose hauv nas (15, 20). Nyob rau hauv lub preexistingmob raum, fructose accelerates kev loj hlob ntawmmob raumnrog cov kev hloov pauv tseem ceeb hauv glomeruli thiab tubulointerstitium (14). Cultured proximal tubular hlwb tau pom los tso tawm cov kab mob cytokines, suav nrog monocyte chemoattractant protein-1 (MCP-1) hauv cov lus teb rau fructose, cov lus teb metabolic tau kho los ntawm uric acid (21).

Cov lus teb rau fructose yog induced tsis tsuas yog los ntawm kev noj haus fructose tab sis kuj los ntawm endogenous zus tau tej cov fructose nyob rau hauv tubular epithelial hlwb. Qhov tseeb, kev tshawb fawb nas pom tau tias ntshav qab zib lossis hypoxia ua raulub raumtubular epithelial hlwb tso tawm ntau lub cytokines inflammatory cytokines, nrog rau NFkB ua kom, IL6 thiab CCL2 kab lus, tag nrho cov uas tau blunted nyob rau hauv fructokinase-tsis muaj nas (5, 6). Cov hlwb endothelial tseem raug txhawb kom tso tawm intercellular adhesion molecule-1 (ICAM-1) teb rau fructose (22). Ib txoj hauv kev zoo tshaj plaws yog qhov muaj peev xwm ua rau txo qis nitric oxide (NO) muaj nyob rau hauv cov hlwb endothelial vim tsis muaj cov neeg pub dawb txo cov fructose-induced ICAM-1 qhia. Cov nyhuv no tau pom tias yog vim qhov tsis sib xws ntawm endothelial NO synthase (eNOS) ua los ntawm fructose-induced oxidative stress (23-25). Fructose induced tiam ntawm uric acid kuj tuaj yeem koom nrog hauv cov txheej txheem no vim tias uric acid ncaj qha cuam tshuam kev ua haujlwm endothelial (16, 26, 27).

CKD tau koom nrog kev ua rau lub raum tsis zoo HYPOXIANyob rau hauv ib txwm physiological mob, lubraummedulla nyob rau hauv ib qho tsis tshua muaj pa oxygen siab nrog ib nrab oxygen siab nyob rau hauv thaj tsam ntawm 10 mus rau 20 mmHg, sib piv nrog rau hauv lub cortex uas yog hais txog 50 mmHg (28). Physiological hypoxia feem ntau nyob ntawm qhov kev thov siab ntawm oxygen los ntawmlub raumtubular hlwb kom tswj tau electrolyte thauj. Cov pa oxygen kuj tseem txwv rau thaj chaw no vim tias cov hlab ntsha tau ua haujlwm nrog lub tshuab hluav taws xob, nyob rau hauv uas oxygen diffuses los ntawm arterial mus rau venous vasa recta thiab tawm sab nraud medulla tsis muaj oxygen (28). Nyob rau hauv cov xwm txheej pathological, qib qis oxygen tau nrawm dua. Piv txwv li, qhov poob ntawm glomerular capillaries nyob rau hauv glomerular sclerosis txo cov ntshav ntws mus rau lub distal peritubular capillaries nrog ntxiv txo cov pa oxygen. Ib yam li ntawd, CKD-associated anemia tuaj yeem txo cov pa oxygen, thaum constriction ntawm efferent arteriole los ntawmintrarenalua kom cov renin angiotensin aldosterone system txo cov ntshav ntws mus rau tubulointerstitial cheeb tsam nrog cov teebmeem zoo sib xws ntawm kev xa oxygen (28). Vim tias cov no yog cov kev sib koom ua ke hauv kev nce qib ntawmkab mob raum, hypoxia yog suav tias yog kev sib koom ua ke mus rau theem kawgmob raum (28, 29).

Covlub raumphysiologically nruab nrog compensatory teb rau hypoxia. Cov txheej txheem tiv thaiv suav nrog kev ua kom muaj qhov tshwm sim ntawm hypoxia-induced factor-1a (HIF-1}a), uas muaj peev xwm txhawb kev qhia ntawm erythropoietin kom nce erythrocytes, thiab induction ntawm vascular endothelial kev loj hlob yam (VEGF) rau inducing angiogenesis (30), ob qho tib si uas pab xa oxygen mus rau hypoxic peripheral cov ntaub so ntswg. Txawm li cas los xij, cov tshuaj tiv thaiv no tuaj yeem dhau los ua kev puas tsuaj nyob rau hauv ntau yam kab mob pathological. Tshwj xeeb, HIF tuaj yeem hloov mus ua profifibrotic nyob rau hauv kev txhawb nqa hypoxia hauv CKD (31). Cov txheej txheem yuav muaj feem cuam tshuam nrog lub peev xwm ntawm HIF kom pom zoo rau glycolysis tshaj mitochondrial ua pa, thiab ua rau muaj kev cuam tshuam rau kev ua pa ntawm mitochondrial.

Kev tsim cov fructose endogenous (32, 33). Txawm li cas los xij, nyob rau hauv qhov teeb meem ntawm kev mob hypoxia, nws zoo li tias mitochondrial kev ua haujlwm yuav raug txo qis, yog li xav tau kev hloov pauv rau glycolysis.

LUB SIJ HAWM WARBURG tau koom nrog hauv CKDLub mitochondria tau ntev tau lees paub tias yog qhov chaw muaj kev ntxhov siab oxidative hauv ntshav qab zib, thiab kev ua kom tsis zoo ntawm mitochondria kuj tseem tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev mob ntshav qab zib (34-36), txawm hais tias tseem muaj qee qhov kev tsis sib haum xeeb (37). Txawm li cas los xij, cov pov thawj tsis ntev los no tau qhia tias kev ua haujlwm ntawm mitochondrial yog qhov zoo dua rau kev txo qis hauv ntshav qab zib, thiab kev kho kom rov zoo li qub mitochondrial kev noj qab haus huv zoo dua qub.lub raum, mob plawv, thiab neuronal tshwm sim (38–42). Raws li nrog cov kev tshawb fawb no, kev sim kev tshawb fawb tau pom tias glycolytic intermediates thiab enzymes yog upregulated nyob rau hauv lubraumCortex hauv hom 2 mob ntshav qab zib mellitus (42). Ib yam li ntawd, metabolites hauv mitochondrial citrate lub voj voog tau txo qis hauv cov neeg mob ntshav qab zib nephropathy piv rau kev noj qab haus huv (43). Cov ntaub ntawv no qhia tau hais tias activated glycolysis yog qhov tseem ceeb tshaj mitochondrial muaj nuj nqi thiab ua lub luag haujlwm pathological hauv ntshav qab zib nephropathy.

Kuj tseem muaj pov thawj tias yuav muaj kev hloov pauv ntawm oxidative kev nyuaj siab rau glycolysis hauv lwm hom CKD. Ib qho piv txwv yog Autosomal dominant polycysticmob raum(ADPKD), uas yog tshwm sim los ntawm kev poob-ntawm-kev hloov pauv hauv PDK1 lossis PKD2 (44). Rowe et al. pom tias kab lis kev cai nas embryonic fifibroblasts (MEFs) muab los ntawm Pkd-/- nas nyiam siv cov piam thaj ntau dua, tab sis tso tawm ntau dua lactate rau hauv kab lis kev cai nruab nrab tshaj li cov hlwb los ntawm cov nas qus (45). Tsis tas li ntawd, Pkd-/- MEFs tsim cov ntsiab lus ATP ntau dua, uas tau cuam tshuam nrog kev tswj hwm ntawm glycolysis enzymes thiab tsuas muaj cov nyhuv me me los ntawm oligomycin, ib qho inhibitor ntawm mitochondrial ATP synthesis, qhia tias ATP yog tsim los ntawm glycolysis, tab sis tsis yog los ntawm mitochondrial. ua pa. Ib yam li ntawd, tus nas tsis muaj Pkd hauv lublub raumtubules, raws li tus qauv nas rau ADPKD, tau nthuav tawm glycolysis ua kom thaum thaiv glycolysis nrog 2DG, cov piam thaj analog, ua tiav kom txo qis tubular cell proliferation, ua rau txo qis hauvraumloj thiab cyst tsim (45, 46).

Kev hloov mus rau glycolysis kuj tau pom nyob rau hauv tus qauv ntawm unilateral ureteral obstruction thiab hauv TGF-b1- kholub raumqauv fifibrosis. Tshwj xeeb, Ding et al. pom tias myofifibroblast activation nyob rau hauv lublub raumNws cuam tshuam nrog kev txhim kho cov piam thaj hauv cov ntshav thiab lactate ntau lawmlub raumuas tuaj yeem txo qis los ntawm kev thaiv glycolysis los ntawm 2-Deoxy glucose kho. Tom qab ntawd nws tau pom tias qhov no tau sawv cev rau TGF b1- nyob ntawm qhov hloov pauv metabolic nyiam glycolysis dhau mitochondrial ua pa. Cov ntaub ntawv no qhia tias cov nyhuv Warburg tuaj yeem ua lub luag haujlwm tseem ceeb hauv cov txheej txheem ntawmlub raumfibrosis (47) .

FRUCTOSE ua ib lub tshuab ua kom muaj kev cuam tshuam ntawm WARBURG hauv CKDKev soj ntsuam uas CKD cuam tshuam nrog kev ua phemintrarenalischemia thiab hypoxia tuaj yeem cuam tshuam loj rauintrarenalmetabolism. Raws li peb tau hais, hypoxia-txuas nrog HIF-1ib qho kev tsim tawm endogenous fructose thiab metabolism. Park et al. tau kawm txog lub luag haujlwm ntawm fructose nrog cov liab qab mole nas, uas tuaj yeem muaj sia nyob ntev dua nyob rau hauv cov xwm txheej hypoxic, thiab pom tias cov txheej txheem rau kev ua siab ntev rau hypoxia yog vim lawv lub peev xwm los tsim fructose endogenously (32). Fructose tuaj yeem metabolized txawm tias muaj cov pa oxygen tsawg thaum nws tuaj yeem muab ob peb biosynthetic intermediates los ntawm ntau txoj hauv kev kom tau raws li qhov kev thov rau kev tiv thaiv ntawm tes (raws li tau tham hauv nqe lus saum toj no).

Txawm li cas los xij, thaum fructose zoo li txhais tau tias yog kev tiv thaiv hauv kev teeb tsa ntawm ischemia, nyob rau hauv cov kab mob pathological fructose tuaj yeem muaj qhov tshwm sim tsis zoo. Mirtchink et al. pom tias fructokinase tau kho nyob rau hauv qhov tsis tshua muaj oxygen raws li HIF lub hom phiaj noob, tab sis nws tau pab txhawb kev loj hlob ntawm lub plawv hypertrophic hauv cov nas thaum lub plawv hypertrophy raug thaiv hauv fructokinase tsis muaj nas (33). Hauvlub raum,endogenous fructose tuaj yeem raug tshem tawm hauv ntau yam kab mob pathological. Andres-Hernando et al. qhia tau hais tias ib qho kev hloov pauv ischemia muaj peev xwm ua rau muaj kev cuam tshuam endogenous fructose hauv lub cevlub raumtubules, thiab dua nws tau pom tias yuav deleterious li thaiv fructose metabolism ameliorates lubmob raumnyob rau hauv ib qho ischemia-reperfusion nas qauv (5).

Lwm qhov chaw nyob qhov twg endogenous fructose tsim nyob rau hauvraumyog siab heev nyob rau hauv mob ntshav qab zib nephropathy. Hauv ntshav qab zib nephropathy muaj tsis yog xwbintrarenalischemia thiab hypoxia, tab sis muaj kev lag luam ntau ntawm cov piam thaj hauv cov tubules ze. Kev nce hauv zos hauv qabzib yog lwm qhov kev txhawb nqa loj rau kev tsim fructose. Raws li fructokinase muaj nyob rau hauv cov tubules ze ze (S1 txog S3), nws zoo li tias cov khoom fructose endogenous yog siab (7). Tseeb, thaiv fructokinase tau pom tias muaj kev tiv thaiv hauv kev sim ntshav qab zib nephropathy (6).

Cov cell tubular proximal feem ntau nyiam lipids tshaj qabzib rau kev tsim hluav taws xob, yog li glycolysis tsis tau ua haujlwm hauv hom cell no. Nws yuav raug suav nrog los ntawm kev tsis sib npaug ntawm cov kev ua haujlwm enzymatic rau glycolysis tshaj cov rau gluconeogenesis (18). Vim tias cov cell tubular proximal yog qhov chaw loj ntawm fructose metabolism hauvraumRaws li qhov no yog qhov uas fructokinase feem ntau qhia, fructose metabolism physiologically txuas nrog gluconeogenesis, tab sis tsis nrog glycolysis (18). Txawm li cas los xij, qhov no tsis yog qhov teeb meem rau cov tubules puas. Nyob rau hauv qhov tseeb, lub puas proximal tubular hlwb feem ntau txuam nrog mitochondrial hloov, ua rau metabolic hloov los ntawm mitochondrial oxidative phosphorylation rau glycolysis nrog lub amplified qhia ntawm glycolytic enzymes (48). Qhov tseem ceeb, thaum fructose metabolized nrog qabzib, kev ua haujlwm ntawm glucokinase yog txhim kho (49-52).

YUAV UA LI CAS YUAV TSUM TAU TXAIS SGLT2 INHIBITORS HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM HAUJ LWM NTAWM GLYCOLYSIS?SGLT2 inhibitors tsis ntev los no tau txais kev saib xyuas los ntawm cov kws kho mob thiab cov kws tshawb fawb txog lawv cov txiaj ntsig kev kho mob loj uas txuas ntxiv dhau nws cov kev tswj glycemic hauv ob qho tib si tsis muaj ntshav qab zib thiab ntshav qab zib.kab mob raumthiab nyob rau hauv cov teeb meem mob plawv cuam tshuam nrog CKD (53, 54). Txawm hais tias cov txheej txheem meej tseem tsis meej, cov kev tshawb fawb tsis ntev los no tau qhia tias qhov kev tiv thaiv kev tiv thaiv yuav raug suav los ntawm kev tiv thaiv kev hloov pauv ntawm cov metabolism hauv daim ntawv lipid oxidation rau glycolysis raws li aberrant glycolysis yuav cuam tshuam nrog epithelial-rau-mesenchymal hloov pauv ntawm cov kab mob sib thooj hauv cov ntshav qab zib. nephropathy (55, 56). Tsis tas li ntawd, SGLT2 inhibitors yuav txo tauintrarenalua hauj lwm los ntawm kev thaiv cov piam thaj uptake, thiab yog li txointrarenalhypoxia nrog kev thaiv ntawm HIF-1 ib qho tsub zuj zuj, thiab nrog rau kev tiv thaiv kev txo qis ntawm klotho, cov xwm txheej uas xav tias yuav txo qis glycolysis (57, 58). Ib qho kev tiv thaiv ntxiv los ntawm SGLT2 inhibition yog ua kom hloov pauv cov roj siv mus rau cov rog rog kom ua rau muaj kev nce ntxiv hauv lipolysis thiab ketogenesis (59). Qhov nce hauv cov ntsiab lus ketone kuj qhia txog kev nce hauv b oxidation thiab txo qis ntawm glycolysis (60), uas tuaj yeem piav qhia ob qho tib si cardioprotective thiab nephroprotective teebmeem (61). Qhov kev txhawb nqa ntawm AMPK thiab sirtuin-1 yog qhov yuav muaj lwm txoj hauv kev rau kev tiv thaiv ntawm SGLT2 inhibitors (62).

Ib qho ntawm cov haujlwm tseem ceeb ntawm SGLT2 inhibitors yog los thaiv kev nqus cov piam thaj rau hauv S1 thiab S2 ntu ntawm cov tubule ze ze, thiab qhov no yuav tsum ua kom txo qis cov piam thaj hloov mus rau fructose. Txij li qee qhov fructokinase tau qhia ntawm qhov chaw (15), qhov no tuaj yeem sawv cev ib txoj hauv kev los thaiv cov nyhuv Warburg. Raws li qhov kev pom zoo no, thaiv fructokinase txo qhov hnyav ntawm ntshav qab zib nephropathy hauv nas (6, 7). Txawm li cas los xij, yav dhau los peb tau hais tias kev thaiv cov piam thaj nkag mus rau hauv ntu S1 thiab S2 ntawm cov tubules ze ze tuaj yeem ua rau cov piam thaj reabsorbed los ntawm S3 ntu, uas tuaj yeem ua rau muaj fructose txaus uas nws cov metabolism los ntawm fructokinase tuaj yeem ua rau tubular. raug mob thiab mobmob raum(63). Hauv kev sib npaug tag nrho, txawm li cas los xij, kev siv SGLT2 inhibitors yuav tsum muaj kev tiv thaivraum.

KEV PAB CUAM RAU GLYCOLYSIS VS. OxIDATIVE METABOLISM hauv MACROPHAGE ACTIVATIONMacrophages koom nrog hauv fructose-inducedlub raumo (14, 15, 22). Muaj ob qhov loj macrophage phenotypes muaj: ib qho pro inflammatory (M1) phenotype uas tso siab rau glycolysis thiab anti-inflammatory / pro-resolving (M2) phenotype uas nyob ntawm oxidative phosphorylation (64, 65). Txij li thaum macrophages qhia Glut5 ntawm lawv qhov chaw (66), thiab fructose txhawb cov macrophages kom tso tawm cov cytokines pro-inflammatory cytokines (67, 68), fructose tej zaum yuav yog ib qho zoo tagnrho roj rau M1 macrophage vim nws lub peev xwm los txhawb glycolysis. Txawm hais tias ntau qhov kev tshawb fawb qhia tias mitochondrial respiratory saw tseem ua haujlwm hauv cov kab mob M1 macrophages, nws tuaj yeem ua haujlwm los tsim cov pa oxygen reactive los tua cov kab mob sib kis uas tsis yog los txhawb ATP synthesis (69).

Nyob rau hauv sib piv, ib txoj kev tshawb no tsis ntev los no qhia tau hais tias oxidative metabolism, tab sis tsis glycolysis, plays lub luag hauj lwm tseem ceeb ntawm macrophage activation nyob rau hauv fructose-inflammation vim thaiv oxidative phosphorylation, tab sis tsis inhibition ntawm glycolysis, suppressed tso tawm pro-inflammatory cytokines (67). Qhov kev tshawb pom tseem ceeb yog tias fructose txhawb nqa glutamine uptake los qhib TCA lub voj voog, ua rau mTORC1 ua kom tso tawm cov kab mob cytokines hauv tib neeg monocytes thiab nas macrophages. Thaum fructose metabolism inhibits aconitase, thiab yog li inhibits TCA voj voog, glutamine metabolism muab a-ketoglutarate uas tuaj yeem hla cov kauj ruam no tso cai rau oxidative phosphorylation tshwm sim (70, 71).

Muab cov lus tseeb no, macrophages yuav siv glycolysis lossis oxidative phosphorylation rau lawv qhov ua kom, thiab cov txheej txheem meej txog yuav ua li cas macrophages xaiv txoj hauv kev metabolic tseem tsis meej. Qhov kev piav qhia muaj peev xwm yog qhov muaj cov pa oxygen yog qhov txiav txim siab raws li cov haujlwm ntawm cytochrome c oxidase kev ua haujlwm txo qis thaum cov pa oxygen concentration poob qis dua 1.0mM (72). Ib yam li ntawd, Semba et al. Tsis ntev los no kuj tau tshuaj xyuas lub luag haujlwm ntawm cov pa oxygen hauv macrophage tsiv teb tsaws thiab pom tias nyob rau hauv qhov hnyav hypoxia, glycolysis yog qhov tseem ceeb thaum cytochrome c oxidase kev ua haujlwm raug thaiv hnyav (73). Nyob rau hauv lem, cytochrome c kev ua ub no hloov nrog oxygen muaj, thiab glycolysis yog kiag li hloov rau oxidative phosphorylation nyob rau hauv aerobic mob.

Ua ke, cov kev tshawb fawb no qhia tias macrophages nyob ntawm ob qho tib si glycolysis lossis oxidative phosphorylation rau lawv txoj kev ua kom, thiab kev xaiv cov txheej txheem metabolic tuaj yeem yog ib feem nyob ntawm qhov muaj oxygen. Nws zoo li glycolysis tsav M1 macrophage activation nyob rau hauv hypoxic mob, whereas oxidative phosphorylation yog siv nyob rau hauv aerobic mob (73). Cov kev tshawb fawb no qhia tias fructose metabolism kuj tuaj yeem cuam tshuam los ntawm kev muaj oxygen, yog li kev ua kom cov metabolism hauv macrophage yuav raug txiav txim los ntawm ob qho tib si fructose concentration thiab oxygen.

Cov lus xausPeb cov kev tshawb fawb qhia tias fructose tuaj yeem ua lub luag haujlwm hauv CKD. Qhov no tuaj yeem tshwm sim tom qab kev noj ntau dhau ntawm fructose los ntawm kev noj zaub mov. Txawm li cas los xij, nws kuj yuav yog qhov tshwm sim ntawm endogenous fructose ntau lawm uas tau tsav los ntawmintrarenalischemia lossis nce kev lag luam ntawm cov piam thaj. Thaum kawg, kev tawm tsam ntawm txoj hauv kev no tuaj yeem piav qhia txog kev tiv thaiv ntawm SGLT2 inhibitors hauv cov ntshav qab zib thiab tsis yog ntshav qab zib CKD.