The Ca2+/calmodulin-dependent protein kinase IIa (Thr286Asp) transgenic mice: a novel mouse model of severe insulin-dependent diabetes

Diabetes mellitus is the leading cause of blindness and end?stage renal disease. To understand the pathogenesis of diabetic complications, suitable animal models for this disease have been needed. The activation ofCa2+? calmodulin?dependent protein kinase II (CaMKII) in pancreatic β?cells has been thought to play a central role in Ca2+?mediated insulin secretion. We generated transgenic mice over expressing the constitutively active?type CaMKIIα (Thr286Asp) in β?cells, which showed very high plasma glucose levels and exhibited the features of diabetic nephropathy and retinopathy. In cDNA microarray analysis osteopontin mRNA increased in CaMKIIα transgenic mice. In quantitative real?time RT?PCR analyses, not only M1 macrophage marker genes but also M2 macrophage marker genes were over expressed in renal cortex of CaMKIIα transgenic mice. The mice were crossed with conditional knockout mice in which platelet?derived growth factor receptor?β gene (Pdgfr?β) was deleted postnatal. The increased oxidative stress in the kidneys of the CaMKII α transgenic mice, which was shown by the increased urinary 8?hydroxydeoxyguanosine excretion and the increased expression of NAD (P) H oxidase 4, was decreased by Pdgfr?β deletion. The CaMKIIα (Thr286Asp) transgenic mice will be valuable as a novel model of severe insulin?dependent diabetes accompanied by an early progression of diabetic micro vascular complications.