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1.
Acta Pharmacol Sin ; 45(5): 1032-1043, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38286833

RESUMO

It is well established that the synthesis of extracellular matrix (ECM) in mesangial cells is a major determinant of diabetic kidney disease (DKD). Elucidating the major players in ECM synthesis may be helpful to provide promising candidates for protecting against DKD progression. tRF3-IleAAT is a tRNA-derived fragment (tRF) produced by nucleases at tRNA-specific sites, which is differentially expressed in the sera of patients with diabetes mellitus and DKD. In this study we investigated the potential roles of tRFs in DKD. Db/db mice at 12 weeks were adapted as a DKD model. The mice displayed marked renal dysfunction accompanied by significantly reduced expression of tRF3-IleAAT and increased ferroptosis and ECM synthesis in the kidney tissues. The reduced expression of tRF3-IleAAT was also observed in high glucose-treated mouse glomerular mesangial cells. We administered ferrostatin-1 (1 mg/kg, once every two days, i.p.) to the mice from the age of 12 weeks for 8 weeks, and found that inhibition of the onset of ferroptosis significantly improved renal function, attenuated renal fibrosis and reduced collagen deposition. Overexpression of tRF3-IleAAT by a single injection of AAV carrying tRF3-IleAAT via caudal vein significantly inhibited ferroptosis and ECM synthesis in DKD model mice. Furthermore, we found that the expression of zinc finger protein 281 (ZNF281), a downstream target gene of tRF3-IleAAT, was significantly elevated in DKD models but negatively regulated by tRF3-IleAAT. In high glucose-treated mesangial cells, knockdown of ZNF281 exerted an inhibitory effect on ferroptosis and ECM synthesis. We demonstrated the targeted binding of tRF3-IleAAT to the 3'UTR of ZNF281. In conclusion, tRF3-IleAAT inhibits ferroptosis by targeting ZNF281, resulting in the mitigation of ECM synthesis in DKD models, suggesting that tRF3-IleAAT may be an attractive therapeutic target for DKD.


Assuntos
Nefropatias Diabéticas , Matriz Extracelular , Ferroptose , Animais , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Nefropatias Diabéticas/metabolismo , Matriz Extracelular/metabolismo , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Humanos , Células Mesangiais/metabolismo
2.
Zhongguo Dang Dai Er Ke Za Zhi ; 12(4): 275-7, 2010 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-20416219

RESUMO

OBJECTIVE: To examine serum levels of interleukin-13 (IL-13) and tumor necrosis factor alpha (TNF-alpha) in children with Mycoplasma pneumoniae (MP) pneumonia. METHODS: Eighty children with MP pneumonia complicated by wheezing or without (n=40 each), 40 children with pneumonia from non-MP infection and 40 healthy children were enrolled. Serum levels of IL-13 and TNF-alpha were measured using ELISA. RESULTS: The serum levels of IL-13 and TNF-alpha in the MP pneumonia group were significantly higher than those in non-MP pneumonia group and the healthy control group (P<0.01). The children with MP pneumonia complicated by wheezing had increased serum levels of IL-13 (214.6 + or - 67.2 ng/L vs 189.6 + or - 52.1 ng/L; P<0.01) and TNF-alpha(0.55 + or - 0.13 ng/mL vs 0.42 + or - 0.16 ng/mL; P<0.01)compared with those without wheezing. CONCLUSIONS: The increase in serum levels of IL-13 and TNF-alpha may play important roles in the pathogenesis of MP pneumonia and wheezing attack in children.


Assuntos
Interleucina-13/sangue , Pneumonia por Mycoplasma/imunologia , Fator de Necrose Tumoral alfa/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pneumonia Bacteriana/imunologia , Sons Respiratórios/imunologia
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