中国病理生理杂志2026，Vol.42Issue(3)：497-510,14.DOI:10.3969/j.issn.1000-4718.2026.03.009
树豆酮酸A衍生物XJ-60通过上调POT1a抑制糖尿病肾病小鼠衰老相关分泌表型和肾纤维化
Up-regulation of POT1a by cajanonic acid A derivative XJ-60 attenuates senescence-associated secretory phenotype and renal fibrosis in mice with diabetic kidney disease
摘要
Abstract
AIM:To investigate the therapeutic potential of XJ-60,a derivative of cajanonic acid A,in atten-uating renal injury in a murine model of diabetic kidney disease(DKD),and to elucidate the underlying mechanisms with a focus on POT1a regulation and telomere damage-associated signaling.METHODS:Eight-week-old db/db mice were randomized into a DKD model group and an XJ-60 treatment group,administered XJ-60 at 50 mg·kg-1·d-1 via oral gavage for 8 weeks,with age-matched wild-type(WT)mice serving as controls(n=6/group).Renal function was evaluated by uri-nary microalbumin(MALB),serum creatinine(Scr),and blood urea nitrogen(BUN).Renal pathology was assessed by hematoxylin and eosin(HE)and Masson's trichrome staining.In vitro,mouse renal tubular epithelial cells(mRTECs)were exposed to high glucose(HG)to establish a cell injury model and divided into normal glucose,HG,HG+XJ-60,and HG+POT1a overexpression groups.RT-qPCR,Western blot,and immunofluorescence were performed to assess telomere length,POT1a expression,and DNA damage response signaling proteins,including checkpoint kinase 1(CHK1),phos-phorylated CHK1(p-CHK1),and γ-phosphorylated histone H2AX(γH2AX).Using these techniques,we also quanti-fied the senescence markers cyclin-dependent kinase inhibitor 1(p21Cip1/Waf1)and cyclin-dependent kinase inhibitor 2A(p16INK4a),along with the fibrosis-associated proteins fibronectin(FN)and collagen type IV(Col-IV).Additionally,se-nescent cells were identified and quantified using senescence-associated β-galactosidase(SA-β-Gal)staining.RE-SULTS:Compared with WT controls,db/db mice exhibited significant renal dysfunction and pathological injury(P<0.05),characterized by tubulointerstitial fibrosis and cellular senescence(P<0.05).These phenotypes were accompa-nied by POT1a downregulation(P<0.05),telomere shortening(P<0.05),and activation of the DNA damage pathway(P<0.05).Treatment with XJ-60 significantly improved renal function,indicated by reduced MALB,Scr,and BUN levels,and alleviated histological injury in db/db mice(P<0.05).Mechanistically,XJ-60 restored POT1a expression and telo-mere length(P<0.05),suppressed CHK1 phosphorylation and γH2AX accumulation(P<0.05),and simultaneously atten-uated renal senescence and fibrosis(P<0.05).Consistently,POT1a overexpression in HG-challenged mRTECs delayed telomere shortening,inhibited DNA damage activation,and alleviated senescence-and fibrosis-associated phenotypes(P<0.05).CONCLUSION:Cajanonic acid A derivative XJ-60 mitigates DKD-associated renal injury in mice,at least in part,by upregulating POT1a to preserve telomere integrity,thereby disrupting the DNA damage-senescence-fibrosis axis.关键词
树豆酮酸A衍生物/糖尿病肾病/细胞衰老/纤维化/端粒/端粒保护蛋白1αKey words
cajanonic acid A derivative/diabetic kidney disease/cellular senescence/fibrosis/telomere/protection of telomeres 1α分类
医药卫生引用本文复制引用
罗荣刚,肖瑛,代云莉,胡丽,冯昭卫,耿召碟,徐韬,廖旭阳,王建塔,郭兵..树豆酮酸A衍生物XJ-60通过上调POT1a抑制糖尿病肾病小鼠衰老相关分泌表型和肾纤维化[J].中国病理生理杂志,2026,42(3):497-510,14.基金项目
国家自然科学基金资助项目(No.82360149) （No.82360149）
