Aim Thromboxane A2（TXA2） is assumed to contribute to the process of renal dysfunction. The pres- ent study was designed to investigate whether terutroban, a specific antagonist of thromboxane/prostaglandin？ （TP） ...Aim Thromboxane A2（TXA2） is assumed to contribute to the process of renal dysfunction. The pres- ent study was designed to investigate whether terutroban, a specific antagonist of thromboxane/prostaglandin？ （TP） receptor, protects against renal damage in 5/6 nephrectomy. Methods C57/BL6 mice were randomly grouped into sham-operated （2K）, 5/6 nephroectomy groups （5/6K-off） and 5/6 nephroectomy treated with ter- utroban （10 mg · kg^-1 · d^-l） groups （Yerutroban）. Renal artery and kidney were collected for vascular function study, Western blot, immunohistochemistry （IHC） assay and enzyme-linked immunosorbent assay （ELISA）, re- spectively. Results Four weeks after the surgery, arterial blood pressure was comparable among the three groups. However mice in terutroban group had higher levels of serum creatinine and lower survival. Compared with 2K groups, 5/6K-off mice had significantly higher levels of renal blood flow as well as a blunted relaxation to acetyl- choline. Production of prostacyclin （PGI2） and thromboxane B2 （ TXB2）, but no prostaglandin E2 （ PGE2）, were significantly increased in the renal artery of 5/6K-off group. Terutroban restored the renal blood flow, but not the acetylcholine-induced relaxation in the renal artery. It is probably due to the blockade effect of terutroban on the smooth muscle since terutroban treatment significantly reduced U46619-induced vasconstriction in renal arteries. Interestingly, terutroban increased the production of TXB2, but not PGI2 or PGE2, in the renal artery. This proba-bly is a compensatory effect on prostaglandins production. In kidney cortex, 5/6K-off group had significantly lower levels of PGE2 and TXB2 when compared with 2 K group. Terutroban markedly increased all three prostaglandins levels. Conclusion Terutroban restores renal artery function, but not renal function in mouse with 5/6 nephrecto- my. It suggests that kidney has more complicated regulations than renal artery. High levels of prostanoids in kid- neys may contribute to renal damage in terutroban group. Further experiments will focus on examining the underly- ing mechanisms.展开更多
Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Here...Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Herein,a mouse model of CKD was established using conventional 5/6 nephrectomy.We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.Methods:Cognitive behavior was assessed using the Morris water maze,novel object recognition test,and fear conditioning test.Further experiments were also conducted to investigate the underlying molecular mechanisms.Results:Our clinical data revealed a decrease in cognitive function among patients with CKD,accompanied by elevated plasma levels of pro-inflammatory cytokines.A positive correlation between cytokine concentrations and serum creatinine levels,as well as a significant positive correlation with cognitive dysfunction,were observed.Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice.Furthermore,20 mg/mL interleukin-6(IL-6)significantly decreased HT22 cell activity in vitro.Further,HT22 cells treated with IL-6 showed increased expression levels of toll-like receptor 4(TLR4)and myeloid differentiation primary response gene 88(MyD88),thereby inducing the nuclear factor kappa-B p65 inflammatory pathway and mitochondria-dependent apoptosis.The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus.TLR4 knockdown antagonized the IL-6-mediated pro-inflammatory and pro-apoptotic effects in HT22 cells.TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites,thus ameliorated cognitive impairment.Conclusion:These results suggest that IL-6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD,ultimately culminate in cognitive impairment.展开更多
文摘Aim Thromboxane A2（TXA2） is assumed to contribute to the process of renal dysfunction. The pres- ent study was designed to investigate whether terutroban, a specific antagonist of thromboxane/prostaglandin？ （TP） receptor, protects against renal damage in 5/6 nephrectomy. Methods C57/BL6 mice were randomly grouped into sham-operated （2K）, 5/6 nephroectomy groups （5/6K-off） and 5/6 nephroectomy treated with ter- utroban （10 mg · kg^-1 · d^-l） groups （Yerutroban）. Renal artery and kidney were collected for vascular function study, Western blot, immunohistochemistry （IHC） assay and enzyme-linked immunosorbent assay （ELISA）, re- spectively. Results Four weeks after the surgery, arterial blood pressure was comparable among the three groups. However mice in terutroban group had higher levels of serum creatinine and lower survival. Compared with 2K groups, 5/6K-off mice had significantly higher levels of renal blood flow as well as a blunted relaxation to acetyl- choline. Production of prostacyclin （PGI2） and thromboxane B2 （ TXB2）, but no prostaglandin E2 （ PGE2）, were significantly increased in the renal artery of 5/6K-off group. Terutroban restored the renal blood flow, but not the acetylcholine-induced relaxation in the renal artery. It is probably due to the blockade effect of terutroban on the smooth muscle since terutroban treatment significantly reduced U46619-induced vasconstriction in renal arteries. Interestingly, terutroban increased the production of TXB2, but not PGI2 or PGE2, in the renal artery. This proba-bly is a compensatory effect on prostaglandins production. In kidney cortex, 5/6K-off group had significantly lower levels of PGE2 and TXB2 when compared with 2 K group. Terutroban markedly increased all three prostaglandins levels. Conclusion Terutroban restores renal artery function, but not renal function in mouse with 5/6 nephrecto- my. It suggests that kidney has more complicated regulations than renal artery. High levels of prostanoids in kid- neys may contribute to renal damage in terutroban group. Further experiments will focus on examining the underly- ing mechanisms.
基金Zhejiang Provincial Outstanding Youth Science Foundation,Grant/Award Numbers:2023C35009,LTGY23H050003,LTGY24H050004Scienceand Technology Plan Project of Wenzhou Municipality,Grant/Award Numbers:Y2020024,Y20210162,Y2023065Wenzhou Medical University,Grant/Award Number:XY2022007。
文摘Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Herein,a mouse model of CKD was established using conventional 5/6 nephrectomy.We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.Methods:Cognitive behavior was assessed using the Morris water maze,novel object recognition test,and fear conditioning test.Further experiments were also conducted to investigate the underlying molecular mechanisms.Results:Our clinical data revealed a decrease in cognitive function among patients with CKD,accompanied by elevated plasma levels of pro-inflammatory cytokines.A positive correlation between cytokine concentrations and serum creatinine levels,as well as a significant positive correlation with cognitive dysfunction,were observed.Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice.Furthermore,20 mg/mL interleukin-6(IL-6)significantly decreased HT22 cell activity in vitro.Further,HT22 cells treated with IL-6 showed increased expression levels of toll-like receptor 4(TLR4)and myeloid differentiation primary response gene 88(MyD88),thereby inducing the nuclear factor kappa-B p65 inflammatory pathway and mitochondria-dependent apoptosis.The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus.TLR4 knockdown antagonized the IL-6-mediated pro-inflammatory and pro-apoptotic effects in HT22 cells.TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites,thus ameliorated cognitive impairment.Conclusion:These results suggest that IL-6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD,ultimately culminate in cognitive impairment.
