Abstract
The immune system is involved in the development of diabetes complications and IgG Fc gamma receptors (FcgRs) are key immune receptors responsible for the effective control of both humoral and innate immunity. We investigated the effects of members of the FcgR superfamily into both the streptozotocin plus high fat-induced type 2 diabetes and high fat diet (HFD) models. FcgRIII−/− diabetic mice and FcgRIIb−/− diabetic mice had elevated levels of serum creatinine compared with wildtype (WT) diabetic mice. Renal histology of diabetic FcgRIII knockout and FcgRIIb knockout mice showed mesangial expansion and GBM thickening; the mechanistic study indicated a higher expression of TGF-β1, TNF-α, and p-NFκB-p65 compared with wild type mouse. The HFD mouse with FcgRIII knockout or FcgRIIb knockout had increased biochemical and renal injury factors, but oxLDL deposition was higher than in FcgRIII−/− diabetic mice and FcgRIIb−/− diabetic mice. In vitro we further examined the mechanism by which the Fc gamma receptor promoted renal injury and transfected glomerular mesangial cells (GMCs) with FcgRI siRNA attenuated the level of TGF-β1, TNF-α expression. In summary, FcgRI knockdown downregulated kidney inflammation and fibrosis and FcgRIIb knockout accelerated inflammation, fibrosis, and the anomalous deposition of oxLDL whereas FcgRIII deficiency failed to protect kidney from diabetic renal injury. These observations suggested that FcgRs might represent a novel target for the therapeutic intervention of diabetic nephropathy.
Highlights
The past few decades have witnessed a marked increase in the prevalence of diabetic nephropathy (DN), which develops in approximately 30% of patients with type 1 diabetes mellitus (T1DM) and 40% of patients with type 2 diabetes mellitus (T2DM)[1, 2]
The data demonstrated that the mean levels of blood glucose, low-density lipoprotein (LDL), Chol and body weight were higher in Fc gamma receptor III (FcgRIII)−/− or FcgRIIb−/− diabetic mice compared with the WT diabetic mice, which implies the beneficial effect of FcgRIII and FcgRIIb on carbohydrate and cholesterol metabolism
The results showed that high glucose, Oxidative LDL (oxLDL)-immune complexes (ICs) and high glucose plus oxLDL-IC increased the expressions of FcgRI, FcgRIIb and FcgRIII compared with normal glucose (Figures 7 and 8), the group of single oxLDL-IC stimulating cell revealing the lower increasing
Summary
The past few decades have witnessed a marked increase in the prevalence of diabetic nephropathy (DN), which develops in approximately 30% of patients with type 1 diabetes mellitus (T1DM) and 40% of patients with type 2 diabetes mellitus (T2DM)[1, 2]. Given the huge healthcare burden related to DN, it is important to identify specific risk factors and the underlying mechanisms involved in this common diabetic microvascular complication. High glucose and hypercholesterolemia are recognized as the two main characteristics of diabetes mellitus as well as important risk factors for the occurrence and development of DN. Previous studies reported that ox-LDL-IC led to the overexpression of collagen IV in mesangial cells through Fc gamma receptor III (FcgRIII), which implied the involvement of FcgRIII in ox-LDL-ICs induced renal fibrosis [8]. IgG immune complexes are recognized by infiltrating and resident cells through specific receptors of the Fc region [9, 10]. This study investigated the involvement of FcgR members (FcgRI, FcgRIIb, and FcgRIII) in high glucose and ox-LDLIC-induced fibrosis and inflammatory injury in diabetic mice
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