中国比较医学杂志2026，Vol.36Issue(5)：1-13,13.DOI:10.3969/j.issn.1671-7856.2026.05.001
ADAM17调控内质网应激在环孢素A诱导的SD大鼠肾纤维化中的机制研究
Mechanistic study of ADAM17 regulation of endoplasmic reticulum stress in cyclosporine A-induced renal fibrosis in SD rats
摘要
Abstract
Objective To investigate the regulatory mechanisms of a disintegrin and metalloproteinase 17(ADAM17)on endoplasmic reticulum stress(ERS)in cyclosporine A(CsA)-induced renal fibrosis(RF),and to identify potential novel therapeutic targets in the progression of RF.Methods A CsA-induced RF model was established in SD rats through gavage.Plasmid transfection and siRNA were employed to overexpress or knock down ADAM17 in vivo.Indices including body weight,urine protein/creatinine ratio(UPCR),serum blood urea nitrogen(BUN),serum creatinine(SCR),cystatin C(Cys-C),transforming growth factor-β1(TGF-β1),and ADAM17 were measured.Pathological changes in kidney tissues were observed with hematoxylin-eosin staining and Masson trichrome staining.Ultrastructural alterations were examined using transmission electron microscopy.Co-expression of ADAM17 and glucose-regulated protein 78(GRP78)was detected by immunofluorescence.mRNA expression of TGF-β1,Smad3,α-smooth muscle actin(α-SMA),collagen type Ⅰ alpha 1 chain(COL1A1),ADAM17,GRP78,inositol-requiring enzyme 1(IRE1)and activating transcription factor 6(ATF6)in kidney tissues were analyzed with RT-qPCR.Protein expressions of ADAM17,Smad3,TGF-β1,α-SMA,COL1A1,and GRP78 were measured by Western blot.Results Compared with the Control-1 group,rats in the Model-1 group exhibited decreased weight(P<0.01),increased UPCR,and significantly higher levels of serum renal function markers(P<0.0001).Morphological examinations revealed pathological changes such as renal interstitial fibrosis.The expression of RF-related indicators TGF-β1 and Smad3 was upregulated(P<0.001),accompanied by abnormal expression of ADAM17 and GRP78(P<0.01).Overexpression of ADAM17(P<0.0001)also led to a decrease in body weight,increased UPCR,and significant increases in serum renal function markers(P<0.01),and pathological changes associated with RF in rats.The expression levels of RF-related indicators,including TGF-β1,Smad3,α-SMA,and COL1A1,were elevated to varying degrees(P<0.05).Meanwhile,the expression of ERS-related factors GRP78,ATF6,and PERK was upregulated to varying degrees(P<0.05).Conversely,knockdown of the ADAM17 alleviated the aberrant expression of the aforementioned indicators to varying degrees(P<0.05).Conclusions ADAM17 significantly promotes fibrosis progression;its dysregulation of ERS may serve as a critical mechanism underlying this pro-fibrotic process.关键词
肾纤维化/ADAM17/内质网应激/GRP78Key words
renal fibrosis/ADAM17/endoplasmic reticulum stress/GRP78分类
医药卫生引用本文复制引用
孟思琪,齐龙宇,高冉冉,刘瑶,韩聪,胡洪贞,周乐,李伟,王一川..ADAM17调控内质网应激在环孢素A诱导的SD大鼠肾纤维化中的机制研究[J].中国比较医学杂志,2026,36(5):1-13,13.基金项目
国家自然科学基金青年科学基金项目(82204881) （82204881）
国家自然科学基金面上项目(82474252,82174179) （82474252,82174179）
山东省医药卫生科技发展计划项目(202103050260) （202103050260）
山东省自然科学基金(ZR2025MS1296). （ZR2025MS1296）
