Cellular and humoral immune responses in the early stages of diabetic nephropathy in NOD mice

Xiao, Xiaoyan; Ma, Bin; Dong, Bin; Zhao, Peng; Tai, Ningwen; Chen, Li; Wong, F. Susan; Li, Wen

doi:10.1016/j.jaut.2008.12.003

Cited by 84 publications

(81 citation statements)

References 30 publications

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“…8,[10][11][12]32 Animal model studies have demonstrated that glomerular levels of IgG increase with the duration of diabetes and correlate with albuminuria and renal inflammatory infiltrate. [33][34][35] Our study reveals glomerular immune deposits and high levels of total and oxidized LDL-specific antibodies in diabetic hypercholesterolemic mice, without differences between apoE and gapoE mice. Further analysis of IgM/IgG and Th1/Th2 ratios did not substantiate changes in lymphocyte responses.…”

Section: Discussionmentioning

confidence: 66%

Fcγ Receptor Deficiency Attenuates Diabetic Nephropathy

López-Parra

Mallavia

López-Franco

et al. 2012

Journal of the American Society of Nephrology

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Among patients with diabetes, increased production of immunoglobulins against proteins modified by diabetes is associated with proteinuria and cardiovascular risk, suggesting that immune mechanisms may contribute to the development of diabetes complications, such as nephropathy. We investigated the contribution of IgG Fcg receptors to diabetic renal injury in hyperglycemic, hypercholesterolemic mice. We used streptozotocin to induce diabetes in apolipoprotein E-deficient mice and in mice deficient in both apolipoprotein E and g-chain, the common subunit of activating Fcg receptors. After 15 weeks, the mice lacking Fcg receptors had significantly less albuminuria and renal hypertrophy, despite similar degrees of hyperglycemia and hypercholesterolemia, immunoglobulin production, and glomerular immune deposits. Moreover, diabetic Fcg receptor-deficient mice had less mesangial matrix expansion, inflammatory cell infiltration, and collagen and a-smooth muscle actin content in their kidneys. Accordingly, expression of genes involved in leukocyte infiltration, fibrosis, and oxidative stress was significantly reduced in diabetic kidneys and in mesangial cells cultured from Fcg receptor-deficient mice. In summary, preventing the activation of Fcg receptors alleviates renal hypertrophy, inflammation, and fibrosis in hypercholesterolemic mice with diabetes, suggesting that modulating Fcg receptor signaling may be renoprotective in diabetic nephropathy.

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Section: Discussionmentioning

confidence: 66%

Fcγ Receptor Deficiency Attenuates Diabetic Nephropathy

López-Parra

Mallavia

López-Franco

et al. 2012

Journal of the American Society of Nephrology

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“…Exposure of proximal tubules to IgG (but not to albumin) resulted in the increased inflammatory response in another study (26). In the diabetic kidney, infiltrates of IgGϩ B cells and IgG deposition (colocalizing with C3 staining, macrophage accumulation, and chemokine expression) were demonstrated in diabetic nonobese and db/db mice, contrary to the control mice (6,35). Histology examination of kidney tissue from human subjects with severe diabetic nephropathy revealed intense linear staining of the extracellular membranes, particularly in tubules for both albumin and IgG.…”

Section: F160mentioning

confidence: 93%

Elevated urinary excretion of immunoglobulins in nonproteinuric patients with type 1 diabetes

Gohda

Walker

Wołkow

et al. 2012

American Journal of Physiology-Renal Physiology

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Increased albuminuria is a hallmark of early diabetic nephropathy, whereas the role of immunoglobulins (Igs), such as IgG (its 1–4 subtypes), IgA, and IgM, different in charge and size, has not been examined in early nephropathy in the past due to lack of a sensitive and reliable method. Our study group consisted of subjects with type 1 diabetes (T1D) and normoalbuminuria ( n = 78), microalbuminuria ( n = 78), and of 75 healthy subjects (HS). A Luminex-based immunoassay (1,000 time more sensitive than nephelometry-based method) was validated for the urine matrix and used for the measurements of IgG1–4, IgA, and IgM in our study groups. The Luminex-based assay detected Igs in 87% of HS subjects and in 100% of T1D subjects. Recovery of known amounts of Igs added to urine was 92–118%. In the normoalbuminuria group, urinary concentrations of albumin, IgG2, IgA, and IgM were significantly higher than in HS, whereas in the microalbuminuria, further elevation of IgG2, IgG4, and IgA was the most pronounced. In all three groups, fractional excretion of Igs was at least 100 times lower than that of albumin. Fractional excretion of IgG2 was the highest among all Igs. We validated a sensitive method for measuring Igs in urine using Luminex. We found that elevated concentrations of Igs, particularly in IgG2 and IgA, is present in subjects with T1D and no proteinuria. Elevation of those particular Ig subtypes suggests a contribution of novel mechanisms in early diabetic nephropathy, different from charge and size barrier impairment.

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“…Macrophages are the major inflammatory cells found in diabetic kidneys and their accumulation is a recognized feature in renal biopsies from diabetic patients (Xiao et al, 2009). In different experimental models of DN, renal macrophage accumulation correlates with the severity of glomerular and tubulointerstitial injury (Chow et al, 2004;Chow et al, 2005).…”

Section: Immune Cellsmentioning

confidence: 99%

“…adriamycin) (Lim et al, 2010). In patients with type 1 diabetes, the presence of nephropathy and proteinuria has been associated with increased activated peripheral blood T cells and also infiltration of T cells into the kidney (Xiao et al, 2009;Moriya et al, 2004;Ichinose et al, 2007), thus suggesting that lymphocyte activation may play a role in early DN. Activated T cells can cause injury directly through cytotoxic effects and indirectly by recruiting and activating macrophages.…”

Section: Immune Cellsmentioning

confidence: 99%