title: The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis.
abstract: Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is a key event in renal interstitial fibrosis and the progression of chronic kidney disease (CKD). Apelin is a regulatory peptide involved in the regulation of normal renal hemodynamics and tubular functions, but its role in renal fibrosis remains unknown. In this study, we examined the inhibitory effects of apelin on transforming growth factor-β1 (TGF-β1)-induced EMT in HK-2 cells, and evaluated its therapeutic efficacy in mice with complete unilateral ureteral obstruction (UUO). In vitro, apelin inhibited TGF-β1-mediated upregulation of α-smooth muscle actin (α-SMA) and downregulation of E-cadherin. Increased levels of phosphorylated Smad-2/3 and decreased levels of Smad7 in TGF-β1-stimulated cells were reversed by apelin co-treatment. In the UUO model, administration of apelin significantly attenuated renal interstitial fibrosis, as evidenced by the maintenance of E-cadherin and laminin expression, and markedly suppressed expression of α-SMA, TGF-β1 and its type I receptor, as well as interstitial matrix components. Interestingly, in UUO mice, there was a reduction in the plasma level of apelin, which was compensated by upregulation of APJ expression in the injured kidney. Exogenous supplementation of apelin normalized the level of plasmatic apelin and renal APJ. In conclusion, our study provides the first evidence that apelin is able to ameliorate renal interstitial fibrosis by suppression of tubular EMT through a Smad-dependent mechanism. The apelinergic system itself may promote some compensatory response in the renal fibrotic process. These results suggest that apelin has potential renoprotective effects and may be an effective agent for retarding CKD progression.
authors.affiliation: Department of Nephrology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xi Cheng District, Beijing, 100050, China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Wang
authors.forename: Zong-Li
authors.initials: ZL
authors.lastname: Diao
authors.forename: Dong-Liang
authors.initials: DL
authors.lastname: Zhang
authors.forename: Jun-Fang
authors.initials: JF
authors.lastname: Zheng
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: Zhang
authors.forename: Jia-Xiang
authors.initials: JX
authors.lastname: Ding
authors.forename: Wen-Hu
authors.initials: WH
authors.lastname: Liu
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005355:Fibrosis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C495199:apelin-13 peptide