1. Qab zib lossis rog? Lub raum Tubular Metabolism tshuaj xyuas hauv Kev Noj Qab Haus Huv thiab Kab Mob
Apr 17, 2023
Abstract
Lub raum yog ib lub cev muaj zog metabolically uas tso siab rau cov hlwb tshwj xeeb ntawm epithelial muaj li ntawm lub raum tubules kom rov nqus tau cov dej lim dej thiab cov kua dej ntau dua. Feem ntau ntawm cov reabsorption no yog kho los ntawm cov tubule proximal, uas yuav tsum muaj ntau lub zog los pab txhawb kev txav mus los. Yog li ntawd, cov tubule ze ze siv fatty acid oxidation raws li nws txoj kev nyiam metabolic, thiab fatty acid oxidation ua rau adenosine triphosphate (ATP) ntau dua li cov piam thaj metabolism. Tom qab lub raum raug mob, kev hloov pauv hauv metabolic ua rau txo qis fatty acid oxidation thiab nce lactate ntau lawm. Qhov kev tshuaj xyuas no tham txog qhov sib txawv ntawm cov metabolic ntawm qhov sib thooj thiab cov tubular ntu ntawm lub raum noj qab haus huv. Tsis tas li ntawd, cov kev hloov pauv hauv metabolic hauv mob raum raug mob thiab mob raum mob tau tham txog, nrog rau cov kev hloov pauv hauv metabolic cuam tshuam li cas rau kev kho tubular thiab kev loj hlob ntawm cov kab mob raum ntev.
Ntsiab lus
proximal tubule; mob raum mob; mob raum mob; fatty acid oxidation; mob raum; raum metabolism;Cov txiaj ntsig Cistanche.
Taw qhia
Lub raum tau txais 25 feem pua ntawm lub siab tso zis thiab lim txog 180 litres dej ib hnub twg tab sis tso tawm tsuas yog 1 - 2 litres. Tsis tas li ntawd, ntau tshaj 1.6 kg ntawm ntsev yog lim, tab sis tsuas yog 3 - 20 g raug tshem tawm. Ntxiv nrog rau cov piam thaj thiab lwm cov kua dej lim dej, ntau lub zog tau siv los khaws cov feem pua ntawm cov dej thiab ntsev. Tib neeg lub raum yog ib lub cev tsis sib xws nrog kwv yees li 1 lab nephrons, txhua tus muaj glomerulus thiab tom qab ib ntu tubular. Cov tubular compartment muaj cov tubules sib thooj (S1 ntu ze tshaj plaws rau glomerulus, S2, thiab S3), cov khoom ntiag tug ntawm Henle, cov tubules distal convoluted, thiab cov ducts sau. Lub raum tubules yog lub luag haujlwm khaws cia 99 feem pua ntawm cov dej thiab cov kua dej hauv glomerular filtrate thiab tswj cov kua qaub-puag. Cov kev cai metabolic thiab substrate nyiam (xws li, qabzib thiab fatty acids) nyob ntawm seb cov tubular ntu.
Lub raum tuaj yeem raug puas tsuaj los ntawm ischemia, co toxins, tshuaj, thiab kab mob, lossis mob ntev los ntawm ntshav qab zib, kub siab, glomerulonephritis, lossis mob raum mob hnyav. Lub raum tubules, tshwj xeeb tshaj yog cov tubules ze, yog qhov chaw raug mob raum mob (AKI) thiab mob raum mob (CKD). Muaj pov thawj muaj zog uas lub raum tubular metabolism tau hloov pauv hauv AKI thiab CKD. Cov ntaub ntawv pov thawj pom tau hais tias kev kho qee qhov kev hloov pauv hauv metabolic no tuaj yeem txo qis kev raug mob lossis txhawb kev rov qab los, tab sis cov lus nug tseem nyob ntawm qhov kev cuam tshuam metabolic twg yog hloov tau thiab tsis zoo. Qhov kev tshuaj xyuas no yuav tham txog dab tsi paub txog cov metabolism hauv lub raum noj qab haus huv, yuav ua li cas cov metabolism hauv tubular hloov pauv hauv lub raum raug mob, thiab cov kev hloov pauv hauv lub raum cuam tshuam li cas rau cov lus nug tsis teb ntawm kev kho tubular thiab kev loj hlob ntawm tubular interstitial fibrosis (ib qho cim ntawm CKD).
Nyem qhov no mus yuavCistanche extract
Metabolism hauv lub raum noj qab nyob zoo
1. Fatty Acid Oxidation
Lub hlwb loj lub luag haujlwm rau lub peev xwm loj reabsorptive ntawm lub raum yog cov tubules ze ze, uas rov ua dua kwv yees li 70 feem pua ntawm cov lim dej thiab dej. Txhawm rau pab txhawb kev thauj cov dej ntau thiab cov kuab tshuaj, cov thauj khoom uas siv ATP ntau ntau yuav tsum tau ua. Mitochondria muaj ntau nyob rau hauv cov tubules ze ze los tsim cov ATP tsim nyog. zoo ib yam li metabolically active cardiomyocytes, proximal tubules yog nyob ntawm fatty acid oxidation (FAO) raws li cov roj qhov chaw muab 106 ATP units, thaum cov piam thaj metabolism muab 36 ATP units (Daim duab 1A). Feem ntau ntawm lub raum sab nrauv, los yog cortex, yog tsim los ntawm cov tubules ze. Raws li ib tug loj tus naj npawb ntawm cov tubules proximal, cov kev tshawb fawb thaum ntxov tau pom tias ob feem peb ntawm oxygen noj nyob rau hauv tib neeg lub raum los ntawm fatty acid oxidation.
Daim duab 1. Metabolism nyob rau hauv cov tsis muaj mob nephron thiab cov tubule proximal. (A) Cov tubules ze ze muaj lub peev xwm gluconeogenic thiab nyiam siv cov roj ntsha oxidation los tsim ATP Los ntawm qhov sib txawv, cov tubules distal tsis muaj peev xwm gluconeogenic tab sis zoo dua los tsim ATP los ntawm glycolysis. (B) Schematic ntawm cov metabolism hauv cov tubule ze ze uas qhia tias cov piam thaj tau coj mus rau sab apical los ntawm SGLT1/2 transporters thiab tso tawm rau sab basal los ntawm CLUT1/2. Fatty acids (FA) hla lub plasma membrane los ntawm CD36, fatty acid binding proteins (FABPand fatty acid thauj proteins (FATP), hloov mus rau hauv acetyl-CoA, thiab thauj mus rau hauv mitochondria los ntawm carnitine shuttle uas muaj carnitine palmitoyl-transferases CPTla thiab CPT2. Beta oxidation ntawm fatty acyl CoA tsim acetyl-CoA uas nkag mus rau hauv lub voj voog TCA (tricarboxylic acid) Oxidation ntawm acetyl-CoA los ntawm TCA tsim NADH uas nkag mus rau hauv electron thauj saw (EIC) los tsim ATP. Tsim nrog BioRen-com .
Fatty acids tuaj yeem coj los ntawm lub raum tubules feem ntau los ntawm CD36 receptors qhia ntawm cov ntshav plasma, tab sis kuj los ntawm fatty acid binding proteins (FABPs) thiab fatty acid thauj proteins (FATPs) (Daim duab 1B). Tsis tas li ntawd, lawv tuaj yeem tsim los ntawm fatty acid synthase hauv cytoplasm thiab kuj los ntawm cov metabolism ntawm phospholipids los ntawm phospholipase A2. Long-chain fatty acids (LCFA) xws li palmitic acid xav tau carnitine shuttle thauj mus rau mitochondria, qhov twg oxidation thiab ATP ntau lawm. Lub carnitine shuttle muaj carnitine palmitoyltransferase 1 (CPT1) nyob rau sab nraud mitochondrial membrane, uas hloov lipid acyl CoA mus rau cov saw ntev acylcarnitine, tso cai txav mus rau mitochondrial matrix. Lub carnitine palmitoyltransferase 2 (CPT2) enzyme ces reconstitutes acyl CoA, uas undergoes -oxidation nyob rau hauv lub mitochondria. Lub synthesized acetyl coenzyme a nkag mus rau lub voj voog tricarboxylic acid (TCA) thiab oxidized, ua rau txo qis ntawm NAD (nicotinamide adenine dinucleotide) thiab FAD (flavin adenine dinucleotide) rau NADH thiab FADH, feem.NADH thiab FADH ces nkag mus rau electron thauj saw (ETC) thiab muab cov khoom siv hluav taws xob los tsim cov electrochemical gradient uas ua rau ATP ntau lawm.
CPT1 yog xav tias yog tus nqi txwv enzyme hauv fatty acid oxidation. muaj peb isoforms ntawm CPT1 (a, b, thiab c), CPT1a yog heev qhia nyob rau hauv lub raum, siab, thiab lwm yam kabmob, thaum CPT1b yog feem ntau hais nyob rau hauv lub cev nqaij daim tawv, lub plawv, thiab cov ntaub so ntswg adipose, thiab CPT1c yog nyob rau hauv lub hlwb. thiab testis. Tsis ntev los no cov kev tshawb fawb ib leeg-cell transcriptome nyob rau hauv cov laus nas thiab tib neeg lub raum tau lees paub qhov tseem ceeb ntawm CPT1a isoform thiab nws cov lus qhia dav dav hauv lub raum.CPT1 yog xav tau rau mitochondrial ntshuam ntawm LCFA tab sis tsis yog rau nruab nrab-chain fatty acids (MCFA). Raws li kev tshawb fawb isotopic labeling, perfused nas ob lub raum tuaj yeem nqa LCFA (palmitate) thiab MCFA (octanoate). Cov kab mob ntev ntev fatty acids (VLCFA) tuaj yeem oxidized los ntawm peroxisomes, tab sis cov organelles tsis muaj cov kab mob ua pa thiab yog li tsis tuaj yeem tsim ATP. Hauv qhov sib piv, cov khoom ntawm peroxisomal oxidation tuaj yeem thauj mus rau mitochondria ntxiv oxidation rau acetyl coenzyme a thiab ATP ntau lawm ntawm ETC. Qhov siab tshaj plaws ntawm peroxisomes nyob rau hauv lub raum yog nyob rau hauv lub proximal tubule, qhia tias proximal tubular fatty acid oxidation (FAO) tej zaum yuav kho los ntawm ob qho tib si mitochondria thiab peroxisomes. Peroxisomal oxidation ntawm cov saw ntev fatty acids xws li palmitic acid tuaj yeem them nyiaj rau kev puas tsuaj mitochondrial oxidation, uas muaj feem cuam tshuam rau lub raum raug mob. Txawm hais tias tag nrho lub raum tubular ntu muaj peev xwm ntawm oxidizing fatty acids, tus nqi ntawm oxidation zoo li ncaj qha ntsig txog cov ntsiab lus mitochondrial, uas yog qhov loj tshaj plaws nyob rau hauv cov tubular ntu thiab cov tubular ntu. Muab qhov txwv tsis pub muaj peev xwm ntawm kev noj qab haus huv cov tubules kom metabolize qabzib, FAO yog qhov nyiam lub zog substrate rau ntu tubular no.
Cistanche ntxiv
2. Glucose Metabolism
FAO tej zaum yuav yog lub zog zoo tshaj plaws rau cov tubules ze, tab sis lub raum yog lub cev tseem ceeb rau cov piam thaj reabsorption, ntau lawm, thiab siv. Feem ntau ntawm cov piam thaj lim dej, tag nrho 180 g ib hnub, rov zoo los ntawm ib qho ntawm ob lub sodium-dependent glucose cotransporters (SGLT) nyob rau ntawm qhov chaw apical ntawm cov tubules proximal.SGLT2 yog qhov tsis tshua muaj affinity, high-volume transporter protein nyob rau hauv feem ntau. nyob rau hauv S1 thiab S2 ntu ntawm cov tubule proximal.SGLT2 khub niam txiv thauj sodium thiab piam thaj hauv qhov sib piv 1: 1 thiab reabsorbs txog li 90 feem pua ntawm cov piam thaj lim. Nyob rau hauv sib piv, SGLT1 yog ib tug high-affinity, low-volume transporter protein nyob rau hauv lub S3 ntu ntawm lub proximal tubule uas thauj sodium thiab qabzib nyob rau hauv ib tug ratio ntawm 2: 1. Nyob rau hauv xyoo tas los no, SGLT2 tau txais kev saib xyuas raws li lub hom phiaj rau ntau cov tshuaj (xws li, empagliflozin thiab dapagliflozin) uas yog nephroprotective thiab cardioprotective txawm nyob rau hauv cov neeg mob uas tsis muaj ntshav qab zib. SGLT2- cov txheej txheem kho kom haum xeeb ntawm kev tiv thaiv CKD thiab lub plawv tsis ua haujlwm yog dhau ntawm qhov kev tshuaj xyuas no tab sis hais txog qhov tseem ceeb ntawm kev tuav lub raum.
Cov piam thaj ntau nkag mus rau hauv lub tubule ze ze, tab sis raws li tau piav qhia dhau los, cov piam thaj me me yog metabolized hauv cov tubule uas tsis muaj kev puas tsuaj. Nyob rau hauv sib piv, GLUT tsev neeg ntawm kev yooj yim transporter proteins nyob rau hauv lub basolateral daim nyias nyias thiab tso cai rau cov qabzib mus rau hauv lub concentration gradient rov qab mus rau hauv kev ncig.GLUT2 yog ib tug transporter pom nyob rau hauv S1 thiab S2 proximal tubule ntu uas phim cov high-ntim, qis- affinity qabzib flux pib los ntawm SGLT2 ntawm apical nto. Ib yam li ntawd, GLUT1 muab txoj hauv kev tawm rau cov piam thaj los ntawm SGLT1 rau hauv ntu S3. Yog li, cov tubules ze ze yog feem ntau ntawm FAO rau lub zog, tab sis cov piam thaj ntau ntau tshwm sim hauv cov hlwb, thiab kev cuam tshuam ntawm cov piam thaj no tau siv los kho CKD thiab lub plawv tsis ua haujlwm.
Lub raum thiab daim siab tsuas yog ob lub cev uas muaj peev xwm tso cov piam thaj mus rau hauv cov hlab ntsha, vim lwm cov ntaub so ntswg tsis muaj qabzib 6-phosphatase, uas yuav tsum muaj rau qabzib -6-phosphate tsim. Glucose tuaj yeem tsim los ntawm glycogenolysis lossis los ntawm gluconeogenesis. Glycogen tau tawg mus rau hauv qabzib-6-phosphate hauv glycogenolysis, tab sis lub raum tsis muaj cov khw muag khoom glycogen tseem ceeb. Hauv gluconeogenesis, substrates xws li lactate, glycerol, alanine, thiab glutamine tuaj yeem ua rau cov piam thaj -6-phosphate ntau lawm. Hauv lub raum, kev tshawb fawb tau pom tias lactate yog qhov tseem ceeb ntawm gluconeogenesis. Cov kev tshawb fawb pib ntsuas lub raum arterial thiab venous glucose concentrations tsis pom muaj ntau qhov sib txawv ntawm cov piam thaj hauv lub raum. Txawm li cas los xij, kev tshawb fawb siv isotopically sau cov suab thaj tau pom tias ob lub raum tsim thiab metabolize ntau cov piam thaj. Cov txheej txheem zoo sib xws hauv tib neeg qhia tias ob lub raum suav txog kwv yees li 25 feem pua ntawm tag nrho cov piam thaj tso tawm rau hauv kev ncig. Hauv cov neeg mob ntshav qab zib mellitus, muaj pov thawj tias gluconeogenesis txuas ntxiv los ntawm ob lub raum thiab lub siab. Cov txiaj ntsig no qhia tias lub raum gluconeogenesis tuaj yeem cuam tshuam nrog hyperglycemia hauv cov neeg mob ntshav qab zib. Hauv cov neeg mob ntshav qab zib mellitus uas muaj kab mob hauv lub raum ntev, kev poob ntawm lub raum gluconeogenic kev ua haujlwm tuaj yeem ua rau lub sijhawm hypoglycemic thiab txo qis kev tshem tawm cov tshuaj insulin vim yog lub raum tsis ua haujlwm.
Herba Cistanche
Lub raum tsim thiab siv cov piam thaj, tab sis cov dej num no nruj me ntsis muab faib ua cov tubule cell tshwj xeeb. Gluconeogenesis raug txwv rau cov tubules ze ze uas qhia txog cov enzymes tseem ceeb uas tsim nyog rau cov txheej txheem no: qabzib -6-phosphatase, phosphoenolpyruvate carboxykinase (PEPCK), thiab fructose-1, 6 -diphosphatase (Daim duab 2). Piv txwv li, nyob rau hauv lub raum noj qab nyob zoo, kev siv cov piam thaj raws li ib tug metabolic roj yog txwv rau lub distal tubules. Glycolysis yog kev hloov pauv ntawm cov piam thaj mus rau pyruvate, uas tuaj yeem txuas ntxiv oxidized lossis metabolized rau lactate ntawm TCA lub voj voog. Glycolytic enzymes xws li hexokinase, phosphofructokinase, thiab pyruvate kinase yog feem ntau qhia nyob rau hauv crude ascending limb, distal, thiab sau tubules. Raws li cov qib enzyme qhia, qabzib oxidation thiab gluconeogenesis ntawm ATP tau qis dua nyob rau hauv cov tubules ze ntawm microdissected nas ntau dua li ntawm cov tubular ntu. Cov kev tshawb fawb tau pom tias cov tubules distal tuaj yeem metabolize qabzib rau lactate txawm nyob rau hauv cov xwm txheej aerobic, thiab lub peev xwm no tau txhim kho zoo heev los ntawm kev ua ntawm antimycin A, uas tiv thaiv oxidative ua pa. Nyob rau hauv sib piv, nyob rau hauv microdissected nas proximal tubules, qabzib tsim me ntsis lactate, thiab antimycin A ua tsis tau tejyam kom induce elevated lactate, qhia hais tias noj qab haus huv cov tubules muaj ib tug txwv muaj peev xwm metabolize qabzib rau lactate. Yog li, cov piam thaj yog tsim los ntawm cov tubule ze ze ntawm gluconeogenesis, thaum lub raum lub raum ntu yog metabolized ntawm glycolysis.
Daim duab 2. Glucose metabolism thiab ntau lawm nyob rau hauv lub raum tubules. Glucose yog metabolized rau qabzib-6-phosphate uas tuaj yeem nkag mus rau hauv txoj kev pentose phosphate lossis metabolized rau pyruvate (glycolysis). Cov enzymes tseem ceeb uas tsim nyog rau glycolysis yog teev nyob rau hauv liab, thiab cov enzymes no feem ntau qhia nyob rau hauv distal tubules ntawm lub raum. Pyruvate tuaj yeem hloov mus rau hauv lactate (anaerobic glycolysis) lossis nkag mus rau mitochondria qhov twg nws hloov mus rau hauv acetyl-CoA los ntawm pyruvate dehydrogenase (PDH) thiab oxidized los ntawm tricarboxylic acid (TCA) lub voj voog. Enzymes cuam tshuam nrog gluconeogenesis tau pom hauv xiav thiab lawv cov lus qhia hauv lub raum raug txwv rau cov tubules ze ze. Phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDK). Tsim nrog BioRender.com.
3. Amino Acid Metabolism
Ze li 70 g ib hnub twg ntawm cov amino acids dawb yog lim los ntawm glomerulus thiab lawv cov reabsorption los ntawm lumen feem ntau yog kho los ntawm cov tubule proximal. Amino acids yog absorbed rau hauv lub raum tubules los ntawm diffusion, yooj yim diffusion, thiab sodium-dependent active thauj. Amino acid transporter proteins yog heev qhia nyob rau ntawm txhuam ciam teb ntawm lub proximal tubule lumen, tab sis basolateral amino acid transporter proteins kuj reabsorb amino acids rau tej hauj lwm. Raws li tau hais los saum no, qee qhov ntawm cov amino acids reabsorbed tuaj yeem ua cov substrates rau cycloisomerization. Tsis tas li ntawd, cov amino acids tuaj yeem nkag mus rau TCA lub voj voog thiab raug oxidized ntawm cov ntsiab lus sib txawv. Branched-chain amino acids (BCAAs), muaj xws li leucine, valine, thiab isoleucine, kuj yog ib qho tseem ceeb ntawm lub zog. BCAAs tau pib ua cov metabolism hauv transaminase los ntawm branched-chain aminotransferase (BCAT) los tsim cov ceg ntoo-kab-keto acids, uas tom qab ntawd oxidatively decarboxylated los ntawm ceg ceg-chain-keto acid dehydrogenase (BCKDH) complex. BCAA metabolites nkag mus rau TCA lub voj voog raws li acetyl coenzyme a lossis succinyl BCAA metabolites nkag mus rau TCA lub voj voog nyob rau hauv daim ntawv ntawm acetyl coenzyme a lossis succinyl coenzyme a, qhov chaw uas lawv raug oxidation. bCAT thiab BCKDH tau qhia thiab ua haujlwm hauv lub raum, qhov twg oxidative flux ntawm BCAA siab dua lwm cov ntaub so ntswg tshwj tsis yog lub plawv thiab xim av rog. Nws kwv yees tias kwv yees li 8-13 feem pua ntawm tib neeg BCAA metabolism tshwm sim hauv lub raum.
Cov metabolism ntawm qee cov amino acids pab txhawb lwm yam kev ua haujlwm lom neeg ywj pheej ntawm kev tsim hluav taws xob, xws li lub luag haujlwm ntawm glutamine metabolism hauv acid / base homeostasis. Glutamine tuaj yeem metabolized los ntawm cov tubule ze ze rau glutamate, uas tig mus rau TCA lub voj voog nruab nrab -ketoglutarate. Cov tshuaj tiv thaiv no kuj tsim cov ammonia, qee qhov nkag mus rau hauv cov zis los ntawm sodium-hydrogen exchanger-3 (NHE3), thiab bicarbonate, uas yog reabsorbed rau hauv kev ncig ntawm basolateral sodium-coupled bicarbonate cotransporter, isomer 1A (NBCe{{ 6}}A). Thaum lub sij hawm acidosis, proximal lub raum tubule metabolism ntawm glutamine los tsim ammonia thiab recycling ntawm bicarbonate yog upregulated los pab tswj cov kua qaub / base homeostasis. Qhov no yog ua tiav los ntawm upregulating glutaminase (lub enzyme uas catalyzes glutamine metabolism) thiab los ntawm kev nce kev qhia ntawm basolateral glutamine transporter proteins kom nce uptake mus rau hauv lub tubule proximal. Cov metabolism ntawm lwm cov amino acids kuj txhawb nqa ammonia thiab bicarbonate reabsorption, tab sis glutamine yog qhov tseem ceeb.
Standardized Cistanche
Lub raum yog qhov chaw tseem ceeb rau cov metabolism ntawm lwm cov amino acids thiab ua lub luag haujlwm tseem ceeb hauv kev lom neeg. Citrulline yog tsim los ntawm enterocytes ntawm txoj hnyuv me, absorbed los ntawm ob lub raum, thiab metabolized rau arginine. Arginine yog ib qho ua ntej ntawm nitric oxide (NO), uas yog ib qho tseem ceeb rau endothelial kev ua haujlwm thiab kev tswj cov ntshav khiav, nrog rau lwm yam teebmeem (kev tiv thaiv kab mob, kev tsim cov protein). Lub raum kuj hloov phenylalanine mus rau tyrosine ntawm phenylalanine hydroxylase, uas yog qhia nyob rau hauv ob lub raum thiab lub siab. Tyrosine plays lub luag haujlwm tseem ceeb hauv kev tsim cov tshuaj neurotransmitters thiab thyroid hormones, thiab kev hloov pauv ntawm phenylalanine rau tyrosine yog txo los ntawm 50 feem pua hauv cov neeg mob uas muaj kab mob hauv lub raum kawg piv rau lub raum ua haujlwm. Cov no tsis yog tib qho piv txwv ntawm qhov tseem ceeb ntawm lub raum amino acid metabolism, uas tau raug tshuaj xyuas ntau dua los ntawm lwm tus. Txawm hais tias cov piam thaj thiab fatty acids yuav yog qhov tseem ceeb ntawm lub zog rau lub raum noj qab haus huv, lub raum amino acid metabolism ua lub luag haujlwm tseem ceeb hauv cov kab mob hauv lub cev.
Cov ntaub ntawv
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