Characterization of diabetic nephropathy in CaM kinase IIalpha (Thr286Asp) transgenic mice.
Detailed studies were performed on diabetic kidneys derived from transgenic mice overexpressing the mutant form (Thr286Asp) of Ca(2+)/calmodulin-dependent protein kinase IIalpha (CaM kinase IIalpha) in pancreatic beta-cells. Kidney weight/body weight ratio, urinary albumin/creatinine ratio, serum BUN level, and mesangial/glomerular area ratio were all significantly higher in transgenic mice than in wild-type mice. cDNA microarray analysis revealed 17 up-regulated genes and 12 down-regulated genes in transgenic kidney. Among up-regulated genes, cyclin D2 (6.70-fold) and osteopontin (2.35-fold) were thought to play important roles in the progression of diabetic nephropathy. Transgenic glomeruli and tubular epithelial cells were strongly stained for osteopontin, a molecule which induces immune response. In quantitative real-time RT-PCR analyses, expressions of not only M1 macrophage marker genes but also M2 macrophage marker genes were elevated in renal cortex of transgenic mice. Overall results indicate that CaM kinase IIalpha (Thr286Asp) transgenic mice serve as an excellent model for diabetic nephropathy.
Suzuki
Hikari
H
First Department of Internal Medicine, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
Kato
Ichiro
I
Usui
Isao
I
Takasaki
Ichiro
I
Tabuchi
Yoshiaki
Y
Oya
Takeshi
T
Tsuneyama
Koichi
K
Kawaguchi
Hiroshi
H
Hiraga
Koichi
K
Takasawa
Shin
S
Okamoto
Hiroshi
H
Tobe
Kazuyuki
K
Sasahara
Masakiyo
M
D019943:Amino Acid Substitution; D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D013912:Threonine / Q000235:genetics / Q000378:metabolism
D000943:Antigens, Differentiation; D012333:RNA, Messenger; C506896:Spp1 protein, mouse; C036763:monocyte-macrophage differentiation antigen; D053495:Osteopontin; D013912:Threonine; D001224:Aspartic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2