Anti-Apoptosis Ntawm Podocytes Thiab Pro-Apoptosis Ntawm Mesangial Cells Rau Telmisartan hauv Kev Kho Mob Raum Mob Raum Mob

TSAB NTAWV

Podocyte puas thiab mesangial cell expansion yog ob qho tseem ceeb pathological tshwm sim ntawm glomerular raug mob nyob rau hauv thaum ntxov mob ntshav qab zib. Telmisartan, raws li angiotensin type 1 (AT1) receptor inhibitor, tuaj yeem txhim kho qib siab glycation kawg (AGE) cov khoom lossis angiotensin Ⅱ (Ang Ⅱ)-induced podocyte raug mob xws li detachment lossis apoptosis. Hauv daim ntawv tam sim no, peb thawj zaug tau lees paub qhov kev tiv thaiv ntawm telmisartan ntawm kev mob ntshav qab zib raum thaum ntxov hauv hom 1 mob ntshav qab zib nas. Telmisartan txo qhov poob ntawm podocin thiab inhibited qhov kev qhia ntawm -SMA, qhia txog nws txoj kev tiv thaiv ntawm podocyte raug mob thiab mesangial proliferation, feem. Ntau qhov nthuav peb tau pom qhov cuam tshuam ntawm telmisartan ntawm lub cell viability thiab apoptosis ntawm podocytes thiab mesangial hlwb nyob rau hauv ib puag ncig-qabzib hauv vitro. Cov nyhuv anti-apoptotic ntawm telmisartan ntawm podocytes tej zaum yuav cuam tshuam rau nws qhov inhibition ntawm swiprosin -1 (ib qho protein uas tuaj yeem kho cov ntshav qabzib ntau hauv podocyte apoptosis) qhia. Thaum telmisartan induced ib tug siab qhia ntawm PPAR nyob rau hauv mesangial hlwb, thiab GW9662 (ib tug PPAR antagonist) ib feem inhibited telmisartan-induced apoptosis thiab txo cov kev muaj peev xwm ntawm mesangial hlwb. Tsis tas li ntawd, cov piam thaj ntau dhau los ntawm PKC 1 / TGF 1 qhia hauv mesangial hlwb tuaj yeem raug thaiv los ntawm telmisartan. Cov ntaub ntawv no muab cov txheej txheem ntawm cov xov tooj ntawm tes kom pom tseeb txog kev tiv thaiv ntawm telmisartan hauv ntshav qab zib raum raug mob.

KEYWORDS

Mob raum mob ntshav qab zib mellitus, podocytes (MeSH: D050199), mesangial cells, telmisartan (PubChem CID: 65, apoptosis)

Nyem qhov no mus yuav cov khoom Cistanche

Taw qhia

Mob raum mob ntshav qab zib mellitus (DKD), paub zoo tias yog kab mob raum mob ua rau mob ntshav qab zib mellitus (DM) hom 1 lossis 2 (Podgórski li al., 2019), tuaj yeem ua rau glomerular filtration rate (GFR) txo qis zuj zus, tom qab ntawd nws thiaj li loj hlob mus rau qhov kawg. -stage mob raum (Hou et al., 2018; Ruiz-Ortega li al., 2020; Cov Kws Tshaj Lij Pab Pawg ntawm Suav Koom Haum ntawm Nephrology, 2021). Muaj ob lub tswv yim uas hyperglycemia mediates ntawm lub raum podocyte raug mob thiab glomerular hauv qab daus daim nyias nyias (GBM) hloov pauv los ntawm mesangial cell expansion lossis proliferation (Anders li al., 2018).

Podocytes, yog cov hlwb tshwj xeeb visceral epithelial, nyob rau hauv cov txheej txheem sab nraud ntawm GBM, uas yog cov txheej txheem ko taw interdigitate ua ib qho kev thaiv qhov kawg los tiv thaiv cov zis tsis muaj protein ntau (Podgórski li al., 2019). Tus naj npawb thiab / lossis qhov ceev ntawm txhua tus glomerulus tau kawm hauv cov neeg mob DM (Papadopoulou-Marketou li al., 2017). Kev raug mob rau cov podocytes ua rau poob ntawm lawv cov khoom nplaum thiab yog qhov ua rau DKD txoj kev loj hlob (Podgórski li al., 2019). Lwm tus yam ntxwv tseem ceeb ntawm podocytes yog cov paub tab podocytes yog cov hlwb tsis muaj zog (Podgórski li al., 2019), (Griffin li al., 2003). Kev poob ntawm podocytes ua rau muaj kev loj hlob ntawm cov hlwb mesangial, txawm li cas los xij, kev poob ntau ntau ua rau glomerular fibrosis thiab nce proteinuria raws li kev denudation ntawm GBM (Fukuda li al., 2012). Kev tswj glycemic tsis zoo tau tshwm sim hauv podocytopathy (Anders li al., 2018), morphological hloov pauv yam ntxwv ntawm podocytes hypertrophy, podocyte epithelial-mesenchymal transdifferentiation (Chang et al., 2017), podocytes detachment (Zhang et al., 20s) Wang et al., 2018a) thiab podocytes poob, uas ua rau cov kev hloov pauv ntawm cov podocytes aberrations ua rau lub detachment ntawm GBM nrog rau qhov glomerulosclerosis.

Mesangial hlwb muaj kev cuam tshuam tseem ceeb rau tsis yog kev hloov pauv ntawm glomerular thiab intraglomerular ncig tab sis kuj yog kev txuag ntawm glomeruli, xws li kev tiv thaiv ntawm glomerular endothelial hlwb thiab tawm ntawm cov tshuaj los ntawm cov ntshav thiab kua dej los ntawm microvessels (Wakisaka li al., 2021). Thickened GBM thiab nthuav mesangial yog pom pom glomerular impairments hauv ntshav qab zib (Papadopoulou-Marketou li al., 2017). GBM thickening yog ib qho histopathological thaum ntxov hauv DKD thiab cuam tshuam los ntawm cov nyiaj tau los tsis zoo thiab kev hloov pauv ntawm extracellular matrix secreted los ntawm endothelial hlwb thiab podocytes (Anders li al., 2018). Hyperglycemia excites mesangial hlwb kom proliferate thiab fabricate matrix (Kriz li al., 2017) los ntawm activation ntawm transforming loj hlob factor- (TGF ), uas ncaj qha ua rau lub transcriptional activation ntawm matrix collagens (Ziyadeh li al., 2000) conducing rau lub expanding mesangial. matrix.

Kev cuam tshuam thaum ntxov nrog kev kho mob hypoglycemic thiab antihypertensive yog qhov zoo los ncua qhov tshwm sim thiab kev loj hlob ntawm DKD (Martins and Norris, 2001). Tshwj xeeb tshaj yog pom zoo rau cov neeg laus ntshav siab nrog DM thiab albuminuria yog angiotensin-hloov enzyme inhibitor (ACEI) lossis angiotensin receptor blocker (ARB) (Liew li al., 2020). Blockade ntawm renin-angiotensin system ameliorates cov lus qhia ntawm ANGPTL2 thiab integrin uas tswj cov glomerular barrier (Tawfik li al., 2021). Yog vim li cas telmisartan raug xaiv yog tias nws tau piav qhia tias muaj txiaj ntsig zoo dua li lwm cov tshuaj ARB hauv kev txo cov proteinuria (Naruse li al., 2019; Guo et al., 2020). Ntxiv mus, telmisartan tuaj yeem txo qis cisplatin-induced nephrotoxicity xws li podocyte apoptosis thiab autophagy-associated protein qhia qib (Malik li al., 2015). Fascinatingly, telmisartan muaj cov yam ntxwv zoo li no coj mus rau hauv tus account nws lub luag haujlwm ntxaib ntawm AT1 receptor thaiv qhov kev txiav txim thiab peroxisome proliferator-activated receptor gamma (PPAR) ib feem agonistic cov cuab yeej (Balakumar li al., 2012). Lub hom phiaj ntawm daim ntawv no yog los tshuaj xyuas qhov kev tiv thaiv ntawm telmisartan ntawm kev raug mob podocyte thiab mesangial expansion nyob rau theem pib ntawm hom 1 DM, raws li.

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Cov khoom siv thiab cov txheej txheem

1. Tsiaj

SD txiv neej nas tau yuav los ntawm SLRC Laboratory Tsiaj Ltd. (Shanghai, Suav). Cov nas tsuag tau nyob ntawm qhov ntsuas kub ntawm 22 ± 2 ° C, txheeb ze av noo ntawm 50-60 feem pua, 12-h lub teeb thiab 12-h tsaus voj voog (lub teeb, 08:00-20 :00, tsaus ntuj, 20: 00–08:00), thiab tso cai pub dawb rau kev noj zaub mov qhuav thiab dej kais. Txhua tus tsiaj tau txais kev saib xyuas tib neeg, thiab cov txheej txheem sim tau pom zoo los ntawm Pawg Saib Xyuas Tsiaj ntawm Naval Medical University.

2. Tus qauv thiab kev kho mob ntshav qab zib

Weight 180–200 g male rats were treated with STZ (Sigma, Deisenhofen, Germany) to induce type 1 diabetes. STZ was dissolved in sterile citrate buffer (pH 4.5) and injected intraperitoneally (65 mg/kg body weight) within 10 min of preparation. The non-diabetic rats initially injected with STZ vehicles served as controls (group Con, n = 10). Diabetes mellitus was confirmed by measuring glucose levels in tail venous blood using a B-glucose analyzer (HemoCue, Angelholm, Sweden) 7 days later. Rats with random blood glucose levels>16.7 mmol / L tau suav nrog hauv kev sim.

Cov nas mob ntshav qab zib tau txais telmisartan (Merck, PHR 1855, 10 mg kg−1 ·d−1 po, pawg DM plus Tel, n=10) lossis tsheb (pab pawg DM, n=10) los ntawm gavage rau 4 lub lis piam. Telmisartan siv nyob rau hauv daim ntawv no yog tau los ntawm Sigma-Aldrich Lub teb chaws Yelemees, Inc., uas nws purity yog 98 feem pua ​​ntxiv (HPLC). Nyob rau tib lub sijhawm, cov ntshav qabzib thiab lub cev hnyav tau raug ntsuas, thiab cov zis kuaj rau kev ntsuas ntau ntawm albuminuria tau sau rau hauv cov kab mob metabolic. Cov nas tsuag tau muab tso rau hauv kev siv tshuaj loog tom qab 4 lub lis piam, lub raum raug tshem tawm thiab hnyav rau kev soj ntsuam histological thiab kev rho tawm cov protein.

3. Urinary Albumin

Cov zis kuaj tau centrifuged ntawm 10,000 rpm rau 5 min kom tshem tawm cov khoom tsis zoo. Lub supernatant tau aliquoted thiab khaws cia ntawm -80 degree C kom txog thaum siv. ELISA cov khoom siv rau cov nas tso zis albumin los ntawm Chondrex (Redmond, WA) tau siv raws li cov chaw tsim khoom cov lus qhia.

4. Creatinine Clearance Rate

Cov khoom siv Creatinine Assay (Nanjing Jiancheng, C011-2-1) tau siv rau kev txiav txim siab ntawm creatinine hauv ntshav thiab zis. Ccr raug xam raws li tus qauv: Ccr=(urinary creatinine * 24 h cov zis ntim) / ( ntshav creatinine * 24 h * 60 min / h) / kawg qhov hnyav (kg).

5. Immunohistochemical thiab TUNEL Staining

Lub raum raug txiav rau hauv ib qho slicing microtome ntawm 7–8 μm, thiab kho nrog 4 feem pua ​​​​paraformaldehyde hauv PBS rau 10 min. Kev thaiv tau ua nrog tsis muaj (PBS, 2 feem pua ​​BSA, 10 feem pua ​​FBS) rau 1 h tom qab 10 min incubation nrog qhov thib ob tsis (PBS, 0.4 feem pua ​​Triton). Thawj cov tshuaj tiv thaiv kab mob tiv thaiv -SMA (Servicebio, GB13044) lossis NPHS2 (Abcam, ab229037) tau raug tsim rau 3 teev ntawm chav tsev kub hauv ib chav humidified. Tom qab ntxuav, cov seem tau incubated nrog Cy3 tshis anti-Nas IgG (H plus L) (Servicebio, GB21301), HRP conjugated tshis anti-Labbit IgG (H plus L) (Servicebio, GB23303), los yog immunofluorescent TUNEL (Servicebio, G15. ) cov tshuaj tiv thaiv nyob rau hauv ib chav ntub dej (tsaus, 37 degree, 1 h). Tom qab ntawd cov ntu tau raug cuam tshuam nrog DAPI (Servicebio, G1012) rau kev kuaj pom ntawm nuclei. Thaum kawg, cov stained seem tau muab tso rau hauv qhov kev tiv thaiv fluorescence quenching sealing kua thiab siv cov fluorescence microscope (NIKON ECLIPSE C1, Nyiv).

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6. Cell Culture

Tib neeg lub raum mesangial hlwb (HRMCs) tau txais los ntawm ScienCell Research Laboratories, Santiago, CA, thiab kab lis kev cai hauv Mesangial Cell Medium (MsCM, ScienCell Research Laboratories). HRMCs tau plated rau ntawm poly-L-lysine coated flask (2 ug / cm2), thiab loj hlob ntawm 37 degree nyob rau hauv ib tug humidified huab cua uas muaj 5 feem pua ​​CO2. Cov hlwb hauv qhov kev sim no tau siv nyob rau hauv 3-4 nqe lus thiab tau kuaj xyuas kom ntseeg tau tias lawv pom cov yam ntxwv tshwj xeeb ntawm cov hlwb mesangial. Nas podocyte cell kab MPC-5 tau txais los ntawm ATCC, Maryland, Tebchaws Meskas. Cov hlwb tau loj hlob ntawm hom I collagen hauv RPMI 1640 (10 feem pua ​​​​FBS) nrog 50 U / ml IFN- ntawm 33 degree mus rau 85 feem pua ​​​​ntawm qhov sib xyaw thiab tom qab ntawd hloov mus rau 37 degree yam tsis muaj IFN- rau 10-14 hnub rau kev sib txawv.

7. Cell Viability and Proliferation Assay

Cell Counting Kit-8 (CCK-8) tau siv los ntsuas kev loj hlob ntawm tes thiab cell viability. Cells tau noob nyob rau hauv txhua qhov dej ntawm 96-cov kab lis kev cai zoo (5 × 103 /well). Tom qab kev kho mob, 10 ul CCK-8 (Beyotime, Shanghai, Tuam Tshoj) tau ntxiv thiab incubated rau 1 h ntawm 37 degree C. Absorbance yog ntsuas siv lub microplate nyeem ntawv (Thermo Fisher Scientific, Waltham, MA, United States) ntawm lub wavelength ntawm 450 nm.

8. Annexin V thiab Propidium Iodide Staining

Cells raug plated thiab loj hlob mus txog rau thaum lawv mus txog 60 feem pua ​​​​ntawm cov confluence, thiab tom qab ntawd kho nrog cov piam thaj siab (50 mmol / L) lossis telmisartan. Tom qab 96 teev, cov hlwb uas tau sau tau raug ntxuav nrog txias PBS thiab rov muab tso rau hauv ib qho kev sib khi tsis zoo. Annexin V-FITC thiab PI (eBioscience, Santiago, CA, United States) tau ntxiv rau lub cellular ncua kev kawm ntawv raws li cov chaw tsim tshuaj paus cov lus qhia, thiab ib tug qauv fluorescence ntawm 10, 000 hlwb tau soj ntsuam los ntawm flow cytometry ua nrog FACScan ( Becton, Dickinson, thiab Tuam Txhab, Franklin, NJ, United States).

9. Western Blotting

Lub raum cortex, HRMCs, thiab MPC-5 tau homogenized hauv cov ntaub so ntswg los yog Cell Protein Extraction Reagent (Beyotime) ntxiv nrog cov protease thiab phosphatase inhibitors (Merck, Whitehouse Station, NJ, United States). Cov qauv raug muab cais rau ntawm 10 feem pua ​​SDS PAGE thiab xa mus rau ib lub hnab ntim nitrocellulose (Pall Corporation, NY, United States). Lub membrane tau thaiv nrog 5 feem pua ​​​​bovine serum albumin thiab blotted nrog cov tshuaj tiv thaiv. Anti-PKC 1 (Cell Signaling Technology, 46,809), anti-swiprosin-1 (Abcam, ab24368), TGF- 1 (Abcam, ab215715), Tubulin (Beyotime, AT819) thiab GAPDH (Beyotime, ) tau siv nyob rau hauv qhov concentration ntawm 1: 1, 000. Proteins tau pom los ntawm kev siv IRDye-conjugated anti-nas lossis anti-luv cov tshuaj tiv thaiv kab mob thib ob (Rockland, Limerick, PA, United States) ntawm 1: 5, 000. Siv ODYSSEY INFRARED IMAGING SYSTEM (LI-COR) los soj ntsuam cov txiaj ntsig.

10. Kev Tshawb Fawb Txog Kev Tshawb Fawb

Cov ntaub ntawv ua tau raug tshuaj xyuas los ntawm Keeb Kwm 6.1 (OriginLab, Northampton, MA) thiab qhia tias txhais tau tias ± SD ntawm tsawg kawg peb qhov kev sim ywj pheej. Kev txheeb xyuas qhov tseem ceeb tau txiav txim siab siv ANOVA. Tus nqi ntawm p < 0.05 tau suav tias yog qhov tseem ceeb.

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Kev sib tham

Telmisartan yog ib qho kev xaiv AT1 receptor blocker uas tau siv rau hauv kev kho mob kom txo tau cov ntshav siab thiab tso zis protein ntau hauv cov neeg mob ntshav siab (Baden li al., 2008; Mann li al., 2009). Ntau qhov kev sim tshuaj tau qhia tias telmisartan muaj txiaj ntsig zoo los txo cov proteinuria hauv cov neeg mob macroalbuminuria thiab ncua kev pib thiab kev loj hlob ntawm ntshav qab zib nephropathy (Makino li al., 2005; Nakamura li al., 2010; Fujita et al., 2011; ., 2011). Hauv txoj kev tshawb fawb tam sim no, kev kho qhov ncauj nrog telmisartan hauv STZ-vim cov kab mob ntshav qab zib mellitus tiv thaiv qhov pib ntawm qhov txawv txav ntawm lub raum thiab tag nrho suav nrog kev txo qis hauv lub cev hnyav, ntshav qabzib, thiab zis protein. Cov txiaj ntsig no tau lees paub tias telmisartan muaj kev tiv thaiv renoprotection hauv cov nas mob ntshav qab zib nephropathy thaum ntxov. Qhov tseem ceeb tshaj, txoj kev tshawb no pom tau hais tias qhov kev tiv thaiv ntawm telmisartan ntawm cov ntshav qab zib glomeruli tau tshwm sim hauv cov tshuaj tiv thaiv apoptotic thiab pro-apoptotic cuam tshuam rau podocytes thiab mesangial hlwb, raws li.

Advanced glycation kawg khoom (AGE) tuaj yeem ua rau podocyte DNA raug mob thiab detachment ib nrab los ntawm kev txhawb nqa ntawm Ang II-AT1R axis, yog li muab cov txiaj ntsig tshiab ntawm telmisartan hauv DKD (Fukami li al., 2013). Nyob rau hauv normotensive, qis-qib proteinuric glomerular kab mob, kev kho mob nrog telmisartan nyob rau hauv thaum ntxov theem ntawm tus kab mob, attenuates glomerular thiab tubulointerstitial puas (Villa li al., 2011). Thiab ntau txoj hauv kev yog tej zaum txuas rau pleiotropic qhov tshwm sim nrog rau kev loj hlob ntawm qhov teeb meem, mammalian lub hom phiaj ntawm rapamycin signaling, protein ubiquitination, Wnt-beta catenin pathway, thiab hypoxia signaling (Villa li al., 2011).

Tsis ntev los no, peb tau tshaj tawm tias swiprosin-1 (Wang li al., 2018b), lwm lub npe rau EF-tes domain muaj 2 (EFhd2), tau ua ib feem tseem ceeb hauv kev nce qib ntawm DKD pib tom qab induction, thaum nws nyob. nyob rau hauv podocytes ntawm nas glomerulus. Swiprosin-1 tsis muaj ameliorated mitochondria-dependent podocyte apoptosis txhawb nqa los ntawm hyperglycemia lossis ntshav qabzib siab los ntawm p38 MAPK qhia txoj hauv kev. Ntawm no, peb kuj pom tias telmisartan inhibited hyperglycemia lossis siab-glucose-induced qhia ntawm swiprosin-1 ob qho tib si hauv vivo thiab hauv vitro, uas qhia txog kev tiv thaiv apoptosis ntawm telmisartan ntawm podocytes tej zaum yuav cuam tshuam nrog kev tswj ntawm swiprosin{ {12}} lus.

Mesangial cell proliferation thiab ntau deposition ntawm extracellular matrix proteins tau ascertained as pab rau txoj kev loj hlob ntawm DKD (Lee li al., 2004). Cov kev tshawb fawb yav dhau los tau pom tias cov piam thaj siab tuaj yeem ua rau muaj kev qhia ntawm mesangial extracellular matrix proteins hauv qab hyperglycemia (Taniguchi li al., 2013). -SMA feem ntau yog siv los sib txawv mesangial hlwb los ntawm lwm cov glomerular hlwb nyob rau hauv STZ-induced ntshav qab zib nas, thiab nce -SMA qhia yuav ua tau lub cim ntawm mesangial hlwb 'phenotypic hloov ntawm lub non-activated theem mus rau proliferative, secretory activated theem (Niu et al., 2014). Ntawm no, peb pom tias telmisartan txo qis -SMA qhia hauv cov ntshav qab zib glomerulus. Tsis tas li ntawd, nws tau raug tshaj tawm tias mesangial cell proliferation muaj qhov cuam tshuam loj rau cov kab mob ntawm DKD (Zeng li al., 2013). Peb cov txiaj ntsig hauv txoj kev tshawb fawb no tau qhia txog lub sijhawm- thiab koob tshuaj-nyob ntawm kev nyuaj siab ntawm telmisartan ntawm mesangial cell proliferation ntsig txog cov yam ntxwv ntawm proapoptotic.

Cov ntaub ntawv pov thawj pom zoo pom zoo tias telmisartan muaj txiaj ntsig zoo dua li losartan hauv ameliorating proteinuria hauv cov neeg mob ntshav siab nrog DKD, uas tej zaum yuav cuam tshuam rau nws lub peev xwm los ua ib feem ntawm PPAR (Bichu li al., 2009). Tsis tas li ntawd, cov kev hloov pauv tau zoo xws li kev tiv thaiv lub raum atrophy thiab fibrosis ntawm telmisartan tau txuas nrog kev txo qis hauv kev qhia ntawm TGF 1 thiab lwm yam proinflammatory thiab profibrotic cytokine noob ntawm PPAR / HGF ua kom (Kusunoki li al., 2012), ywj siab. ntawm Ang II hom 1 receptor blockade. Ntawm no, peb kuj pom telmisartan tshwj xeeb qhib PPAR noob qhia nyob rau hauv mesangial hlwb, thiab cov pro-apoptotic nyhuv tshwm sim los ntawm telmisartan rau mesangial hlwb yuav alleviated los ntawm PPAR inhibitors.

PKC 1 yog ib qho ntawm cov tsev neeg nthuav dav ntawm serine-threonine kinases uas hloov ntau yam ntawm cov cellular kev loj hlob los ntawm substrate-specific phosphorylation (Newton, 1995). Nws tau raug tshaj tawm tias tsis tsuas yog nce PKC kev ua haujlwm tab sis kuj nws cov qib mRNA tau pom hauv tib neeg mob ntshav qab zib nephropathy biopsies (Langham li al., 2008). Hyperglycemia-induced PKC qhia thiab ua kom muaj pleiotropic cov teebmeem hauv cov hlwb mesangial, nrog rau kev txhawb nqa ntau dhau ntawm ECM cov proteins (Brownlee, 2001). Cov kev tshawb fawb tau pom tias inhibition ntawm PKC attenuates glomerular hypercellularity thiab extracellular matrix expansion hauv db/db nas thiab glomerular dysfunction hauv STZ-rats (Ishii li al., 1996; Koya li al., 2000). Ib yam li ntawd, PKC inhibitor attenuated platelet-derived growth factor (PDGF)-tsav mesangial cell proliferation thiab collagen ntau lawm (Tokuyama li al., 2011). Hauv peb txoj kev tshawb fawb, telmisartan txo qis kev tswj hwm ntawm PKC 1 mRNA thiab cov protein qhia hauv cov hlwb hyperglycemia-stimulated mesangial. Tsis tas li ntawd, TGF 1 qhia hauv mesangial hlwb raug ntxias los ntawm cov piam thaj siab kuj tuaj yeem cuam tshuam los ntawm telmisartan.

Ob AT1 thiab AT2 receptors, paub zoo tias yog xya transmembrane-spanning G protein-coupled receptors, tau cloned thiab pharmacologically illustrated (Touyz thiab Berry, 2002). Cov AT1 receptors tuaj yeem xaiv antagonized los ntawm telmisartan, thaum AT1 receptor blockers tuaj yeem ua rau muaj kev qhia ntawm AT2 receptors (Touyz thiab Berry, 2002). Cov kev tshawb fawb tau pom tias AT1 receptors tawm dag zog los ntawm kev txwv kev loj hlob ntawm tes, thiab los ntawm kev ua rau apoptosis (Horiuchi li al., 1997; Touyz li al., 1999). Ntxiv mus, AT2 receptors induce cell apoptosis nyob rau hauv ib tug tshwj xeeb conformation los ntawm p38 MAPK-mediated apoptotic signaling (Miura thiab Karnik, 2000). Hauv peb daim ntawv tam sim no, kev qhia ntawm AT1 thiab AT2 mRNA tsis hloov pauv hauv kab lis kev cai mesangial hlwb txhawb nrog telmisartan lossis hyperglycemia. Yog li, telmisartan-induced mesangial cell apoptosis thiab txo qis ntawm PKC 1 yuav tsis raug kho los ntawm AT1 thiab AT2 receptors.

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Hauv kev xaus, telmisartan txo qis glomerular raug mob thaum ntxov hauv hom 1 mob ntshav qab zib nas los ntawm inhibiting podocyte apoptosis thiab txhawb mesangial apoptosis. Cov nyhuv antiapoptotic ntawm telmisartan hauv podocytes tej zaum yuav cuam tshuam rau nws qhov inhibition ntawm swiprosin -1 qhia, lub sijhawm no, cov nyhuv proapoptotic ntawm cov hlwb mesangial yog ib feem cuam tshuam nrog nws cov nyhuv agonistic ntawm PPAR. Tsis tas li ntawd, telmisartan xaiv tau thaiv qhov kev qhia ntawm PKC 1 / TGF 1 hauv cov hlwb mesangial tab sis tsis nyob hauv podocytes. Cov kev tshawb fawb Advanced yog tsim nyog los piav qhia qhov sib txawv tab sis muaj txiaj ntsig zoo ntawm telmisartan ntawm podocytes thiab mesangial hlwb thiab cov hauv paus molecular mechanisms.

Xin Wei 1, Yabin Ma2, Ya Li 3, Wenzhao Zhang4, Yuting Zhong5, Yue Yu6, Li-Chao Zhang5, Zhibin Wang4 thiab Ye Tu2

1 Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, Suav teb,

2 Department of Pharmacy, Shanghai East Tsev Kho Mob, Tongji University, Shanghai, Suav teb,

3 Department of Clinical Pharmacy, Clinical Trial Center, Thawj Tsev Kho Mob ntawm Shandong First Medical University thiab Shandong Provincial Qianfoshan Tsev Kho Mob, Jinan, Tuam Tshoj,

4 Lub Tsev Haujlwm Saib Xyuas Kev Kho Mob Tseem Ceeb, Tsev Kawm Ntawv ntawm Kev Kho Mob, Naval Medical University, Shanghai, Suav,

5 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, Suav teb,

6 Lub Tsev Kho Mob Vascular Disease, Shanghai TCM-Integrated Tsev Kho Mob, Shanghai, Suav