title: Effect of Antifibrotic MicroRNAs Crosstalk on the Action of N-acetyl-seryl-aspartyl-lysyl-proline in Diabetes-related Kidney Fibrosis.
abstract: N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous antifibrotic peptide. We found that suppression of AcSDKP and induction of dipeptidyl peptidase-4 (DPP-4), which is associated with insufficient levels of antifibrotic microRNA (miR)s in kidneys, were imperative to understand the mechanisms of fibrosis in the diabetic kidneys. Analyzing streptozotocin (STZ)-induced diabetic mouse strains, diabetic CD-1 mice with fibrotic kidneys could be differentiated from less-fibrotic diabetic 129Sv mice by suppressing AcSDKP and antifibrotic miRs (miR-29s and miR-let-7s), as well as by the prominent induction of DPP-4 protein expression/activity and endothelial to mesenchymal transition. In diabetic CD-1 mice, these alterations were all reversed by AcSDKP treatment. Transfection studies in culture endothelial cells demonstrated crosstalk regulation of miR-29s and miR-let-7s against mesenchymal activation program; such bidirectional regulation could play an essential role in maintaining the antifibrotic program of AcSDKP. Finally, we observed that AcSDKP suppression in fibrotic mice was associated with induction of both interferon-γ and transforming growth factor-β signaling, crucial molecular pathways that disrupt antifibrotic miRs crosstalk. The present study provides insight into the physiologically relevant antifibrotic actions of AcSDKP via antifibrotic miRs; restoring such antifibrotic programs could demonstrate potential utility in combating kidney fibrosis in diabetes.
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Swayam Prakash
authors.initials: SP
authors.lastname: Srivastava
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.|Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ishigaki
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.|Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology &Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.|Division of Anticipatory Molecular Food Science and Technology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007668:Kidney / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000473:pathology; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D035683:MicroRNAs; D009842:Oligopeptides; D016212:Transforming Growth Factor beta; D016220:Fibroblast Growth Factor 1; D007371:Interferon-gamma; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; C058504:goralatide