NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy

Du, Pengchao; Fan, Baoxia; Han, Hongya; Zhen, Junhui; Shang, Jin; Wang, Xiaojie; Li, Xiang; Shi, Weichen; Tang, Wei; Bao, Chanchan; Wang, Ziying; Zhang, Yan; Zhang, Bin; Wei, Xinbing; Yi, Fan

doi:10.1038/ki.2013.113

Cited by 124 publications

(106 citation statements)

References 46 publications

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“…NOD2 was upregulated in HFD-induced and STZ-induced diabetic mice and kidney biopsies from patients with T2DM 154 . Furthermore, NOD2 was upregulated in podocytes treated with high glucose, AGEs, TNF, or LTA (TGFβ), and Nod2 -/-mice were protected from hyperglycaemia-induced nephrin expression 154 .…”

Section: [H2] Involvement Of Nlrs [H3] Nod2mentioning

confidence: 98%

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Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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Section: [H2] Involvement Of Nlrs [H3] Nod2mentioning

confidence: 98%

“…Furthermore, NOD2 was upregulated in podocytes treated with high glucose, AGEs, TNF, or LTA (TGFβ), and Nod2 -/-mice were protected from hyperglycaemia-induced nephrin expression 154 . Thus, NOD2 links renal injury to inflammation and podocyte insulin resistance in diabetic nephropathy 154 .…”

Section: [H2] Involvement Of Nlrs [H3] Nod2mentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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“…In particular, the cytoplasmic signaling complexes, commonly called inflammasomes, are under intense investigation (15)(16)(17)(18)(19).…”

Section: How Cells Recognize and Respond To Danger Signalsmentioning

confidence: 99%

How the Innate Immune System Senses Trouble and Causes Trouble

Hato

Dagher

2015

Clinical Journal of the American Society of Nephrology

133

111

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The innate immune system is the first line of defense in response to nonself and danger signals from microbial invasion or tissue injury. It is increasingly recognized that each organ uses unique sets of cells and molecules that orchestrate regional innate immunity. The cells that execute the task of innate immunity are many and consist of not only "professional" immune cells but also nonimmune cells, such as renal epithelial cells. Despite a high level of sophistication, deregulated innate immunity is common and contributes to a wide range of renal diseases, such as sepsis-induced kidney injury, GN, and allograft dysfunction. This review discusses how the innate immune system recognizes and responds to nonself and danger signals. In particular, the roles of renal epithelial cells that make them an integral part of the innate immune apparatus of the kidney are highlighted.

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“…50 Vegfb contributes to IR by fatty acids transport in skeletal muscle. 51 Inhibition of Vegfb signaling decreases glucose intolerance, ameliorates dyslipidaemia preserves islet cyto-architecture and enhances b-cell function.…”

Section: E998099-8 Volume 6 Issues 5-6 Isletsmentioning

confidence: 99%

“…18,41 Interestingly, these upregulated genes play a key role in inflammatory diseases of pancreas as well as other organ systems. [42][43][44][45][46][47][48][49][50][51] Some of the notable genes includes Adam17 also known as TNF-a converting enzyme regulates inflammatory cellular processes implicated in renal diseases and metabolic inflammation. 42,43 APOE increases the risk of Alzheimer diseases and is both anti-inflammatory as well as proinflammatory in neuroinflammation.…”

Section: E998099-6mentioning

confidence: 99%

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

Singh¹,

Ganneru²,

Malakapalli³

et al. 2014

Islets

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WNIN/GR-Ob mutant rat is a novel animal model to study metabolic syndrome (obesity, insulin resistance, hyperinsulinemia, impaired glucose tolerance and cardiovascular diseases). We have investigated the islet characteristics of obese mutants at different age groups (1, 6 and 12 months) to assess the islet changes in response to early and chronic metabolic stress. Our data demonstrates altered islet cell morphology and function (hypertrophy, fibrotic lesions, vacuolation, decreased stimulation index, increased TNFa, ROS and TBARS levels) in mutants as compared to controls. Furthermore, network analysis (gene-gene interaction) studied in pancreas demonstrated increased inflammation as a key factor underlying obesity/metabolic syndrome in mutants. These observations pave way to explore this model to understand islet adaptation in response to metabolic syndrome.

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NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy

Cited by 124 publications

References 46 publications

Innate immunity in diabetes and diabetic nephropathy

Innate immunity in diabetes and diabetic nephropathy

How the Innate Immune System Senses Trouble and Causes Trouble

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

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