Journal Article

Cholecystokinin Plays a Novel Protective Role in Diabetic Kidney Through Anti-inflammatory Actions on Macrophage: Anti-inflammatory Effect of Cholecystokinin

NISHIMORI, Hisakazu, SHIKATA, Kenichi, KAJITANI, Nobuo, KODERA, Ryo, NISHISHITA, Shingo, OKADA, Shinichi, HIROTA, Daisho, TAKATSUKA, Tetsuharu, MIYAMOTO, Satoshi, OGAWA, Daisuke, MAKINO, Hirofumi, USUI KATAOKA, Hitomi, MIYASAKA, Kyoko, ADAM UCHIDA, Haruhito, SASAKI, Motofumi, SATO, Chikage, FUNAKOSHI, Akihiro

2012

Overview

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.

• Publisher: American Diabetes Association
• Subject: Allografts / Animals / Biological and medical sciences / Bone marrow / Cell activation / Chemokines, CC / Chemotaxis / Chemotaxis - drug effects / Cholecystokinin / Cholecystokinin - genetics / Cholecystokinin - metabolism / Complications / Creatinine / Diabetes / Diabetes mellitus / Diabetes Mellitus - metabolism / Diabetes. Impaired glucose tolerance / Diabetic nephropathies / Diabetic nephropathy / DNA microarrays / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Gene expression / Gene Expression Profiling / Gene Expression Regulation - physiology / Glucose / Inflammation / Inflammation - metabolism / intercellular adhesion molecule 1 / Intercellular Adhesion Molecule-1 - genetics / Intercellular Adhesion Molecule-1 - metabolism / Kidney / Kidney - metabolism / Kidneys / Macrophages / Macrophages - physiology / Male / Medical sciences / Metastases / Mice / Mice, Knockout / Nephropathy / NF-kappa B - genetics / NF-kappa B - metabolism / octapeptides / Pathogenesis / Physiological aspects / Receptor, Cholecystokinin B - genetics / Receptor, Cholecystokinin B - metabolism / Receptors, Cholecystokinin - genetics / Receptors, Cholecystokinin - metabolism / Sincalide - analogs & derivatives / Sincalide - pharmacology / Stem cell transplantation / Tumor necrosis factor- alpha / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - metabolism