title: Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin.
abstract: Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. shikata@md.okayama-u.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Kyoko
authors.initials: K
authors.lastname: Miyasaka
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okada
authors.forename: Motofumi
authors.initials: M
authors.lastname: Sasaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Kodera
authors.forename: Daisho
authors.initials: D
authors.lastname: Hirota
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kajitani
authors.forename: Tetsuharu
authors.initials: T
authors.lastname: Takatsuka
authors.forename: Hitomi Usui
authors.initials: HU
authors.lastname: Kataoka
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishishita
authors.forename: Chikage
authors.initials: C
authors.lastname: Sato
authors.forename: Akihiro
authors.initials: A
authors.lastname: Funakoshi
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Nishimori
authors.forename: Haruhito Adam
authors.initials: HA
authors.lastname: Uchida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D019742:Chemokines, CC; D002633:Chemotaxis / Q000187:drug effects; D002766:Cholecystokinin / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000235:genetics / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000378:metabolism; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C090019:8-sulfocholecystokinin octapeptide; C511142:Ccl28 protein, mouse; D019742:Chemokines, CC; D016328:NF-kappa B; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D002766:Cholecystokinin; D012844:Sincalide