中山大学学报（医学科学版）2023，Vol.44Issue(6)：931-942,12.
磷酸二酯酶5在肾脏纤维化中的保护作用
Phosphodiesterase 5 Inhibitors Attenuate Unilateral Ureteral Obstruction-Induced Renal Fibrosis
摘要
Abstract
[Objective]To investigate whether phosphodiesterase(PDE)5 inhibitors sildenafil(SIL)or LW1646 pre-vented renal interstitial fibrosis induced by unilateral ureteral obstruction(UUO).[Methods]Male C57BL/6 mice were ran-domly divided into four groups(n =6),namely the Sham group,7UUO group,7UUO+SIL group and 7UUO+LW1646 group.Sildenafil(SIL)or LW1646,or vehicle was administered 1 hour before surgery,and the mice were continuously treated once daily(i.g.,50 mg/kg)for 7 days.The obstructed kidneys were harvested on day 7.Hematoxylin-eosin(HE)and Masson's staining was used to examine renal histology.Immunoblotting and RT-qPCR were used to detect the expres-sion levels of protein and mRNA for fibrosis,apoptosis,endoplasmic reticulum(ER)stress,autophagy,and pro-fibrotic factors.Human proximal tubule epithelial cells(HK-2)were treated with TGF-β1 for 48 hours or tunicamycin for 24 hours,respectively,to evaluate whether cyclic guanosine monophosphate(cGMP)or PDE5 inhibitors prevents ER stress and pro-fibrotic responses.[Results]At the 7th days after UUO,the body weight of the mice showed a significant decrease(P<0.000 1)compared with that in the sham group.The obstructed kidneys showed a significant tubular dilation and inter-stitial inflammation.The levels of protein and mRNA expression in apoptosis,ER stress,autophagy-related protein and pro-fibrotic factors were also markedly increased in UUO mice(P<0.05).In contrast,SIL or LW1646 treatment was asso-ciated with attenuated tubular dilation,infiltration of inflammatory cells and collagen content in the obstructed kidney of the mice.The protein and mRNA expression levels of renal TGF-β1 were markedly decreased,and the protein expression levels of apoptosis,endoplasmic reticulum stress,and autophagy markers were also significantly downregulated by PDE5 inhibitors.In HK-2 cells,TGF-β1 induced increased expression levels of fibronectin and BiP,which was at least partial-ly reversed by cGMP,a product of PDE inhibition.Additionally,PDE5 inhibitors were found to modulate aberrant levels of autophagy and apoptosis.[Conclusion]In conclusion,PDE5 inhibitors,in particular,LW1646,can alleviate the progres-sion of fibrosis by improving ER stress,apoptosis and autophagy as well as downregulating protein and mRNA expression of TGF-β1.关键词
磷酸二酯酶5/肾脏纤维化/单侧输尿管结扎术/内质网应激/小鼠Key words
PDE5 inhibitor/renal fibrosis/UUO/ER stress/mouse分类
医药卫生引用本文复制引用
翟庆娴,李蒙,隆罗莎,梁柏恩,王蔚东..磷酸二酯酶5在肾脏纤维化中的保护作用[J].中山大学学报（医学科学版）,2023,44(6):931-942,12.基金项目
国家自然科学基金(82270744) （82270744）
广州市科技计划项目(202201011621) （202201011621）
