Aberrant Recruitment and Activation of T Cells in Diabetic Nephropathy

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Abstract

Background/Aims: Recent evidence has shown that an inflammatory process is involved in the development and progression of diabetic nephropathy. This study examined the impact of activated intrarenal lymphocytes in this inflammatory process. Methods: We studied T cell recruitment in mice with streptozotocin (STZ)-induced diabetes by flow cytometry and immunohistochemistry. The kidney biopsy specimens from patients with type 2 diabetes mellitus and diabetic nephropathy were evaluated by immunohistochemistry. Results: In flow cytometry, intrarenal CD3+ T cells were significantly increased in proteinuric mice at 20 weeks after STZ injection. However, the population of T cells and B cells in diabetic spleen was not different from that of control mice. Immunohistochemistry also showed a marked infiltration of interstitial CD4+, CD8+ T cells in diabetic kidney. Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) mRNA expression was significantly increased in diabetic mouse kidney compared with controls. Interestingly, flow cytometry analysis of kidney-derived mononuclear cells from diabetic mice showed significantly increased production of IFN-γ and TNF-α by CD3+ T cells. Type 2 diabetic patients also showed a marked increase in CD4+, CD8+ and CD20+ cells in interstitium, and the number of CD4+ and CD20+ cells correlated with the amount of proteinuria. Conclusion: Our results clearly showed that aberrant intrarenal infiltration and the activation of T cells in interstitium are the underlying immunopathological mechanisms of diabetic kidney injury.

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Pathologic classification of diabetic nephropathy.

Thijs W Cohen Tervaert, Antien Mooyaart, Kerstin Amann … (2010)

Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.

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Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes.

John C. Pickup (2004)

There is increasing evidence that an ongoing cytokine-induced acute-phase response (sometimes called low-grade inflammation, but part of a widespread activation of the innate immune system) is closely involved in the pathogenesis of type 2 diabetes and associated complications such as dyslipidemia and atherosclerosis. Elevated circulating inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 diabetes, and several drugs with anti-inflammatory properties lower both acute-phase reactants and glycemia (aspirin and thiazolidinediones) and possibly decrease the risk of developing type 2 diabetes (statins). Among the risk factors for type 2 diabetes, which are also known to be associated with activated innate immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such as fatigue, sleep disturbance, and depression, are likely to be at least partly due to hypercytokinemia and activated innate immunity. Further research is needed to confirm and clarify the role of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 diabetes is a primary abnormality or partly secondary to hyperglycemia, obesity, atherosclerosis, or other common features of the disease.

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Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.

Fiona Chow, Elyce Ozols, David J Nikolic-Paterson … (2004)

Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.

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Author and article information

Journal

Journal ID (publisher-id): AJN

Journal ID (nlm-ta): Am J Nephrol

Journal ID (doi): 10.1159/issn.0250-8095

Title: American Journal of Nephrology

Publisher: S. Karger AG

ISSN (Print): 0250-8095

ISSN (Electronic): 1421-9670

Publication date Subscription-year: 2012

Publication date (Print): February 2012

Publication date (Electronic): 25 January 2012

Volume: 35

Issue: 2

Pages: 164-174

Affiliations

^aDivision of Nephrology, Department of Internal Medicine and ^bDepartment of Pathology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, and ^cDivision of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Korea

Author notes

*Sang-Ho Lee, Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Sangil-dong, Gangdong-gu, Seoul (Korea), Tel. +82 1 440 6121, E-Mail rulale@dreamwiz.com

Article

Publisher ID: 334928 Other ID: Am J Nephrol 2012;35:164–174

DOI: 10.1159/000334928

PubMed ID: 22286547

SO-VID: eed9f945-5bf4-4437-86c7-6c4da0c0f942

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date accepted : 07 November 2011

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Figures: 6, Tables: 4, Pages: 11

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Aberrant Recruitment and Activation of T Cells in Diabetic Nephropathy

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Abstract

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Karger: Nephrology

Most cited references 21

Pathologic classification of diabetic nephropathy.

Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes.

Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.

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