TY - JOUR
T1 - Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage
T2 - Anti-inflammatory effect of cholecystokinin
AU - Miyamoto, Satoshi
AU - Shikata, Kenichi
AU - Miyasaka, Kyoko
AU - Okada, Shinichi
AU - Sasaki, Motofumi
AU - Kodera, Ryo
AU - Hirota, Daisho
AU - Kajitani, Nobuo
AU - Takatsuka, Tetsuharu
AU - Kataoka, Hitomi Usui
AU - Nishishita, Shingo
AU - Sato, Chikage
AU - Funakoshi, Akihiro
AU - Nishimori, Hisakazu
AU - Uchida, Haruhito Adam
AU - Ogawa, Daisuke
AU - Makino, Hirofumi
PY - 2012/4
Y1 - 2012/4
N2 - 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-a 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.
AB - 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-a 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.
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U2 - 10.2337/db11-0402
DO - 10.2337/db11-0402
M3 - Article
C2 - 22357963
AN - SCOPUS:84859534363
SN - 0012-1797
VL - 61
SP - 897
EP - 907
JO - Diabetes
JF - Diabetes
IS - 4
ER -
