NDLI: Negative regulatory responses to metabolically triggered inflammation impair renal epithelial immunity in diabetes mellitus

Content Provider	Springer Nature Link
Author	Chen, Nelson K. F. Chong, Tsung Wen Loh, Hwai Liang Lim, Kiat Hon Gan, Valerie H. L. Wang, Marian Kon, Oi Lian
Copyright Year	2012
Abstract	Diabetes mellitus is characterized by chronic inflammation and increased risk of infections, particularly of tissues exposed to the external environment. However, the causal molecular mechanisms that affect immune cells and their functions in diabetes are unclear. Here we show, by transcript and protein analyses, signatures of glucose-induced tissue damage, chronic inflammation, oxidative stress, and dysregulated expression of multiple inflammation- and immunity-related molecules in diabetic kidneys compared with non-diabetic controls. Abnormal signaling involving cytokines, G-protein coupled receptors, protein kinase C isoforms, mitogen-activated protein kinases, nuclear factor-κB (NFκB), and Toll-like receptors (TLR) were evident. These were accompanied by overexpression of negative regulators of NFκB, TLR, and other proinflammatory pathways, e.g., A20, SOCS1, IRAK-M, IκBα, Triad3A, Tollip, SIGIRR, and ST2L. Anti-inflammatory and immunomodulatory molecules, e.g., IL-10, IL-4, and TSLP that favor TH2 responses were strongly induced. These molecular indicators of immune dysfunction led us to detect the cryptic presence of bacteria and human cytomegalovirus in more than one third of kidneys of diabetic subjects but none in non-diabetic kidneys. Similar signaling abnormalities could be induced in primary human renal tubular epithelial (but not mesangial) cell cultures exposed to high glucose, proinflammatory cytokines and methylglyoxal, and were reversed by combined pharmacological treatment with an antioxidant and a PKC inhibitor. Our results suggest that diabetes impairs epithelial immunity as a consequence of chronic and inappropriate activation of counter-regulatory immune responses, which are otherwise physiological protective mechanisms against inflammation. The immune abnormalities and cryptic renal infections described here may contribute to progression of diabetic nephropathy.
Starting Page	587
Ending Page	598
Page Count	12
File Format	PDF
ISSN	09462716
Journal	Journal of Molecular Medicine
Volume Number	91
Issue Number	5
e-ISSN	14321440
Language	English
Publisher	Springer-Verlag
Publisher Date	2012-11-14
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Diabetes mellitus Inflammation Immune homeostasis Renal epithelium Bacterial infection Cytomegalovirus Molecular Medicine Human Genetics Internal Medicine
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Molecular Medicine Genetics (clinical)

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