Tubulointerstitial inflammation plays an important role in the progression of diabetic nephropathy(DN),and tubular epithelial cells(TECs)are crucial promoters of the inflammatory cascade.Exchange protein activated by cAMP(Epac)has been shown to suppress the angiotensin Ⅱ(Ang-Ⅱ)-induced release of inflammatory cytokines in tubular cells.However,the role of Epac in TEC-mediated tubulointerstitial inflammation in DN remains unknown.We found that administering the Epac agonist 8-pCPT-2'-O-Me-cAMP(8-O-cAMP)to db/db mice inhibited tubulointerstitial inflammation characterized by macrophage infiltration and increased inflammatory cytokine release and consequently alleviated tubulointerstitial fibrosis in the kidney.Furthermore,8-O-cAMP administration restored CCAAT/enhancer binding protein β(C/EBP-β)expression and further upregulated the expression of Suppressor of cytokine signaling 3(SOCS3),while inhibiting p-STAT3,MCP-1,IL-6,and TNF-α expression in the kidney cortex in db/db mice.And in vitro study showed that macrophage migration and MCP-1 expression induced by high glucose(HG,30 mM)were notably reduced by 8-O-cAMP in human renal proximal tubule epithelial(HK-2)cells.In addition,8-O-cAMP treatment restored C/EBP-β expression in HK-2 cells and promoted C/EBP-β translocation to the nucleus,where it transcriptionally upregulated SOCS3 expression,subsequently inhibiting STAT3 phosphorylation.Under HG conditions,siRNA-mediated knockdown of C/EBP-β or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on the release of MCP-1.In contrast,SOCS3 overexpression inhibited HG-induced activation of STAT3 and MCP-1 expression in HK-2 cells.These findings indicate that Epac activation via 8-O-cAMP ameliorates tubulointerstitial inflammation in DN through the C/EBP-β/SOCS3/STAT3 pathway.

Wen-xia Yang;Yu Liu;Shu-min Zhang;Hua-fen Wang;Yi-fei Liu;Jia-lu Liu;Xiao-hui Li;Meng-ru Zeng;Yu-zhang Han;Fu-you Liu;Lin Sun;Li Xiao

Department of Nephrology,Hunan Key Laboratory of Kidney Disease and Blood Purification,The Second Xiangya Hospital,Central South University,Changsha 410011,China

中国药理学报（英文版）

[1]Wen-xia Yang;Yu Liu;Shu-min Zhang;Hua-fen Wang;Yi-fei Liu;Jia-lu Liu;Xiao-hui Li;Meng-ru Zeng;Yu-zhang Han;Fu-you Liu;Lin Sun;Li Xiao-.Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy)[J].中国药理学报（英文版）,2022(03):659-671

Tubulointerstitial,pCPT

Epac,activation,ameliorates,tubulointerstitial,inflammation,diabetic,nephropathy,plays,important,role,progression,DN,tubular,epithelial,cells,TECs,are,crucial,promoters,inflammatory,cascade,Exchange,protein,activated,by,cAMP,has,been,shown,suppress,angiotensin,Ang,induced,release,cytokines,However,mediated,remains,unknown,We,found,that,administering,agonist,Me,db,mice,inhibited,characterized,macrophage,infiltration,increased,consequently,alleviated,fibrosis,kidney,Furthermore,administration,restored,CCAAT,enhancer,binding,EBP,further,upregulated,Suppressor,signaling,SOCS3,while,inhibiting,STAT3,MCP,cortex,And,vitro,study,showed,migration,high,glucose,HG,mM,were,notably,reduced,human,renal,proximal,tubule,HK,In,addition,treatment,promoted,translocation,nucleus,where,transcriptionally,subsequently,phosphorylation,Under,conditions,siRNA,knockdown,partially,blocked,inhibitory,effect,contrast,overexpression,These,findings,indicate,through,pathway

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