Higher urinary IgM excretion in type 2 diabetic nephropathy compared to type 1 diabetic nephropathy

Bakoush, Omran; Tencer, Jan; Tapia, Juan Carlos; Rippe, Bengt; Torffvit, Ole

doi:10.1046/j.1523-1755.2002.00108.x

Cited by 49 publications

(42 citation statements)

References 24 publications

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“…Although urinary excretion is not a significant route of mAb elimination in healthy subjects, renal excretion of therapeutic mAbs may occur, as it does for endogenous proteins in DM, leading to increased It is known that moderate CKD leads to the urinary excretion of endogenous proteins, such as albumin, that are normally conserved (27). Furthermore, larger proteins, such as IgG (mol radius 5.5 nm) or IgM (mol radius 12 nm) that have limited renal elimination, are known to have higher transport across the glomerular filter with compromised renal function and DN (9). The increased size and density of larger pores, along with increased density of shunts in the glomerular capillary wall, leads to increased concentrations of larger molecules in the urine.…”

Section: Discussionmentioning

confidence: 99%

“…Although the prevalence of microalbuminuria and macroalbuminuria is significant with T2DM, only a limited number of studies have evaluated the alteration in renal elimination and urinary concentrations of proteins and macromolecules such as IgG (9,10). In one study, Pima Indians with T2DM and DN demonstrated a greater than twofold increase in urinary IgG concentrations compared to individuals without significant microalbuminuria (10).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Chadha

Morris

2015

AAPS J

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Abstract. The objective of this research was to assess the effects of type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) on the pharmacokinetics of human IgG (hIgG), an antibody isotype, in Zucker diabetic fatty (ZDF) rats. Furthermore, the specific role of T2DM in the altered disposition of hIgG was evaluated by treating diabetic rats with pioglitazone, while the role of chronic kidney disease (CKD) was assessed using 5/6 nephrectomized Sprague Dawley rats. ZDF male (lean non-diabetic control and obese diabetic) and pioglitazone-treated ZDF rats were studied at ages 12-13 weeks (only DM was present), and at ages 29-30 weeks (progression to DN). All animals were dosed with 1 mg/kg of hIgG intravenously (IV) or subcutaneously (SC). ZDF rats had significantly higher blood glucose concentrations and urinary albumin excretion compared to control rats. Significant increases in total clearance (2.5-fold) and renal clearance (100-fold) of hIgG were observed; however the major increase in total clearance was due to increased non-renal clearance. Greater changes in urinary albumin excretion and total and renal clearances of IgG (3.5-fold and 300-fold, respectively) were observed with progression to DN. SC bioavailability of hIgG in all animal groups was similar (>84%). With pioglitazone-treatment, diabetic animals remained euglycemic and treatment was able to reverse the clearance changes, although incompletely. In the CKD group, no difference in hIgG clearance was observed when compared with controls. In conclusion, the increased clearance of hIgG in ZDF diabetic animals, reversal by pioglitazone treatment and lack of effect of CKD, demonstrate the influence of T2DM on hIgG pharmacokinetics.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Chadha

Morris

2015

AAPS J

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“…According to the SEM images of a gold-coated probe (radius of tip apex is 35 nm), and according to the dimensions of a cross linker SPDP (~0.7 nm in length) and an antibody (IgM, 24 nm in length) [23], the diameter of the tip contact area is ~120 nm, which correlates to approximate one pixel (125 nm) in a 4×4 µm 2 affinity map. The antibody modified tip scans pixel by pixel to achieve an affinity map.…”

Section: Discussionmentioning

confidence: 99%

Profiling TRA-1-81 antigen distribution on a human embryonic stem cell

Qiu

Xiang

et al. 2008

Biochemical and Biophysical Research Communications

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Human embryonic stem (hES) cells hold great promise in regenerative medicine. Although hES cells have unlimited self-renewal potential, they tend to differentiate spontaneously in culture. TRA-1-81 is a biomarker of undifferentiated hES cells. Quantitative characterization of TRA-1-81 expression level in a single cell helps capture the "turn-on" signal and understand the mechanism of early differentiation. Here we report on our examination of TRA-1-81 distribution and association on a hES cell membrane using an atomic force microscope (AFM). Our results suggest that aggregated distribution of TRA-1-81 antigen is characteristic for undifferentiated hES cells. We also evaluated the TRA-1-81 expression level at ~17800 epitopes and ~700 epitopes per cell on an undifferentiated cell and a spontaneously differentiated cell, respectively. The method in this study can be adapted in examining other surface proteins on various cell types, thus providing a general tool for investigating protein distribution and association at the single cell level.

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“…These findings may be relevant to the pathogenesis of proteinuria in diabetic states. Diabetic nephropathy is associated with structural alterations that contribute to the increased permeability of the glomerular capillary wall to macromolecules (21)(22)(23)(24)(25). The cellular mechanisms leading to loss of permselectivity during progression of diabetic nephropathy are not well characterized.…”

Section: Discussionmentioning

confidence: 99%

ZΟ-1 Expression and Phosphorylation in Diabetic Nephropathy

et al. 2006

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Cellular mechanisms responsible for the loss of capillary wall permselectivity in diabetic nephropathy are not well characterized. ZO-1 is a junctional protein involved in the assembly and proper function of a number of tight junctions and is also expressed at the junction of podocytes with the slit diaphragm. We investigated the effect of diabetes and high glucose concentration on the expression of ZO-1 in animal models of both type 1 and 2 diabetes and in rat glomerular epithelial cells. In diabetic animals, immunohistochemistry and Western blotting showed decreased expression of ZO-1 in glomeruli. Immunogold electron microscopy revealed redistribution of ZO-1 from the podocyte membrane to the cytoplasm in the diabetic animals. Exposure of rat glomerular epithelial cells to high glucose resulted in a decrease in the intensity of ZO-1 staining and redistribution of ZO-1 from the membrane to the cytoplasm, changes that are attenuated by blockade of the angiotensin II type 1 receptor. ZO-1 protein expression and serine and tyrosine phosphorylation of ZO-1 were also decreased in cells exposed to high glucose. These findings suggest that alterations in the content and localization of ZO-1 may be relevant to the pathogenesis of proteinuria in diabetes. Diabetes 55:894 -900, 2006 D iabetic nephropathy is characterized by proteinuria and progressive fibrosis, resulting in a decline in kidney function in humans and experimental models of diabetes. Proteinuria is one of the most important prognostic risk factors for kidney disease progression (1). Cellular and molecular mechanisms underlying the loss of glomerular permselectivity in diabetic nephropathy and other proteinuric states are under intense investigation. Recent studies have identified mutations in the genes encoding podocyte structural proteins nephrin, podocin, CD2AP, neph-1, and ␣-actinin 4, which result in changes in glomerular permeability (2). ZO-1 ␣Ϫ, an 80 -amino acid truncated isoform of the 225-kD tight junction protein ZO-1, is highly expressed within the podocyte in the cytoplasmic aspect of the foot process membrane, adjacent to the insertion of the slit diaphragm (3-5). It links some of the slit diaphragm proteins through its PDZ (PSD-95/discs-large/ZO-1) domains to the actin cytoskeleton. Thus, changes in the expression or properties of ZO-1 may accompany renal diseases associated with proteinuria, including diabetic nephropathy. Studies in humans and experimental animals highlighted the importance of poor glycemic control in the development of the functional and structural changes in the kidney during the evolution of diabetic nephropathy (1,6 -10). Hyperglycemia and exposure of cultured cells to high glucose induce phenotypic modifications of cells that result in tissue injury (11)(12)(13)(14)(15). This study explored the expression of ZO-1 in two models of diabetes and the effect of glucose on ZO-1 expression and phosphorylation in cultured rat glomerular epithelial cells (GECs). RESEARCH DESIGN AND METHODSAnimals were used in accordance with ...

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Higher urinary IgM excretion in type 2 diabetic nephropathy compared to type 1 diabetic nephropathy

Cited by 49 publications

References 24 publications

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Profiling TRA-1-81 antigen distribution on a human embryonic stem cell

ZΟ-1 Expression and Phosphorylation in Diabetic Nephropathy

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