Deletion of platelet-derived growth factor receptor-beta improves diabetic nephropathy in Ca2+/calmodulin-dependent protein kinase II alpha (Thr286Asp) transgenic mice

作者：Suzuki H; Usui I^*; Kato I; Oya T; Kanatani Y; Yamazaki Y; Fujisaka S; Senda S; Ishii Y; Urakaze M; Mahmood A; Takasawa S; Okamoto H; Kobayashi M; Tobe K; Sasahara M

来源：Diabetologia, 2011, 54(11): 2953-2962.

DOI：10.1007/s00125-011-2270-x

• Knockout mice
• Mouse model
• Nephropathy
• Oxidative stress

The activation of platelet-derived growth factor receptor-beta (PDGFR-beta) signalling is increased in the glomeruli and tubules of diabetic animals. In this study, we examined the role of PDGFR-beta signalling during the development of diabetic nephropathy.
We recently generated pancreatic beta cell-specific Ca2+/calmodulin-dependent protein kinase II alpha (Thr286Asp) transgenic mice (CaMKII alpha mice), which show very high plasma glucose levels up to 55.5 mmol/l and exhibit the features of diabetic nephropathy. These mice were crossed with conditional knockout mice in which Pdgfr-beta (also known as Pdgfrb) was deleted postnatally. The effect of the deletion of the Pdgfr-beta gene on diabetic nephropathy in CaMKII alpha mice was evaluated at 10 and 16 weeks of age.
The plasma glucose concentrations and HbA(1c) levels were elevated in the CaMKII alpha mice from 4 weeks of age. Variables indicative of diabetic nephropathy, such as an increased urinary albumin/creatinine ratio, kidney weight/body weight ratio and mesangial area/glomerular area ratio, were observed at 16 weeks of age. The postnatal deletion of the Pdgfr-beta gene significantly decreased the urinary albumin/creatinine ratio and mesangial area/glomerular area ratio without affecting the plasma glucose concentration. Furthermore, the increased oxidative stress in the kidneys of the CaMKII alpha mice as shown by the increased urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the increased expression of NAD(P)H oxidase 4 (NOX4), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) was decreased by Pdgfr-beta gene deletion.
The activation of PDGFR-beta signalling contributes to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion in CaMKII alpha mice.

• 出版日期2011-11