Cellular and humoral immune responses in the early stages of diabetic nephropathy in NOD mice
Introduction
Diabetic nephropathy is the leading cause of end-stage renal failure in young people and affects about 40% of individuals with long-standing type 1 diabetes [1]. Current therapy, which includes treatment for hyperglycemia, hypertension and dyslipidemia can slow the rate of progression of diabetic nephropathy [2], but eventually end-stage renal failure will still occur in a proportion of patients [3]. Therefore, the effects of currently used treatments must be maximized and identification of new strategies and additional therapeutic targets for treating diabetic nephropathy will be important.
Many factors are involved in the pathogenesis of diabetic nephropathy, which in humans is defined by a progressive rise in albuminuria, together with increasing blood pressure, leading to a fall in glomerular filtration and ultimately end-stage renal failure [3]. Microalbuminuria may occur as early as 5 years after diagnosis of diabetes [3]. Structural abnormalities include glomerular basement membrane thickening, increased number of mesangial cells and mesangial expansion [4]. Metabolic factors, such as the formation of advanced glycation end products and increased flux through the polyol pathways, have been implicated [5]. In addition, growth factors (transforming growth factor TGF-β, insulin-like growth factor IGF-1 and vascular endothelial growth factor VEGF) may also play a role [5], [6]. Although the pathogenesis of diabetic nephropathy is not considered to be primarily immune mediated, nevertheless studies examining renal biopsies in patients with type 1 diabetes have noted T cell infiltration of the juxtaglomerular apparatus [7], [8]. Macrophages have also been detected in kidney sections from patients with diabetic nephropathy although no distinction was made between patients with type 1 or type 2 diabetes [9].
To facilitate dissection of pathogenesis of diabetic nephropathy, a variety of experimental rat and mouse models have been used, many of which relate to type 2 diabetes. In the present study, we focused on the non-obese diabetic (NOD) mouse model that develops spontaneous autoimmune diabetes similar to human type 1 diabetes [10]. Many studies of diabetic nephropathy were performed in chemically-induced diabetic animal models and NOD mice have not been studied much in terms of diabetic nephropathy, perhaps because of the potentially long and variable time to onset of diabetes [11]. However, a few studies have shown that NOD mice could develop renal pathology after the onset of diabetes [12], [13]. To test the hypothesis that immune responses are involved in the development of diabetic nephropathy, we investigated cellular and humoral immune parameters in spontaneous diabetic NOD mice.
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Animals
Female NOD/Caj mice were used in this study. All the mice were housed in individually-ventilated filter cages with autoclaved food under specific pathogen-free (SPF) conditions with a 12-h dark/light cycle. The use of the animals and the procedures applied in this study were approved by the Institutional Animal Care and Use Committee of Yale University.
Determination of diabetes and diabetic nephropathy
NOD mice were observed for diabetes development by weekly screening for glycosuria. Diabetes was confirmed following 2 consecutive readings of
Cellular immune responses in diabetic kidneys
To investigate whether cellular immune responses are involved in the pathogenesis of diabetic nephropathy, we examined mononuclear cell infiltration in glomeruli with confocal microscopy at monthly intervals after the development of diabetes. All the kidneys were perfused before preparation of tissue sections. We found that CD4+ (Fig. 1B–D, F–H) and CD8+ (Fig. 1J–L) T cells were present in the glomeruli in diabetic mice. Dendritic cells (CD11c+) were also present in the infiltrates, in close
Discussion
Our study has shown that, firstly, in the early stages of diabetes in the NOD mouse, both T and B cells infiltrate the glomeruli. Secondly, we have demonstrated that serum components from diabetic NOD mice, but not non-diabetic NOD mice, bind to normal kidney sections, indicating the presence of autoantibodies to the kidney. These autoantibodies only develop after the mice become diabetic and appear to be directed towards renal endothelial cells and the glomerular basement membrane. Thirdly, we
Acknowledgements
Xiaoyan Xiao is a scholarship recipient from the China Scholarship Council (2007-102113). This study was supported by an innovative partnership grant to Li Wen and F. Susan Wong from the JDRF (19-2006-1075). We are grateful to Arthur Hand (University of Connecticut) for the electron microscopy work, Octavian Hengariu for measurement of insulin autoantibodies, Jan Czyzyk for help with independent evaluation of nephropathy and Bin Lu for help with animal care.
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F.S. Wong and L. Wen contributed equally to this study.