The Inflammasomes in Kidney Disease

Anders, Hans‐Joachim; Muruve, Daniel A.

doi:10.1681/asn.2010080798

Cited by 305 publications

(269 citation statements)

References 133 publications

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“…[40][41][42] Inflammasome activation is seen in activated myeloid cells 43 and has also been recently implicated in development of renal diseases, 44 including DN. 44,45 Because our data showed that IL-1b and IL-18 gene expression was significantly increased in the macrophages of diabetic miR-146a 2/2 mice, we also examined inflammasome activation. Gene expression analysis showed significantly increased expression of NLRP3 in miR-146a 2/2 diabetic macrophages ( Figure 7A).…”

Section: Increased Inflammasome Activation In Mir-146a-deficient Macrmentioning

confidence: 99%

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Bhatt

Lanting

Jia

et al. 2015

JASN

149

126

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Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a 2/2 mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a 2/2 than in the kidneys of wild-type mice. Notably, miR146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1b and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a 2/2 mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism in miR-146a 2/2 mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN. 27: 227727: -228827: , 201627: . doi: 10.1681 Diabetic nephropathy (DN) is the leading cause of CKD and ESRD. 1-6 Development and progression of DN involve a complex interplay among metabolic, hemodynamic, growth, and inflammatory factors. 1,3,[7][8][9][10][11][12][13] The progressive decline in renal function during DN is a result of a multitude of pathologic changes in the kidneys, including glomerular and tubular hypertrophy, macrophage infiltration, extracellular matrix (ECM) accumulation in multiple renal cells, mesangial expansion, endothelial dysfunction, and podocyte injury. 1,3,[7][8][9][10][11][12][14][15][16] These pathologic changes clinically manifest as proteinuria and a steady deterioration in GFR. 3,4,16 Identification of molecular pathways that contribute to the pathophysiology of DN is imperative for the development of new therapeutic strategies. J Am Soc NephrolConversely, identification of factors that exert adaptive and protective roles in the early stages of DN can be exploited to prevent progression to ESRD.

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Section: Increased Inflammasome Activation In Mir-146a-deficient Macrmentioning

confidence: 99%

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Bhatt

Lanting

Jia

et al. 2015

JASN

149

126

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“…These results are also consistent with previous studies suggesting IL-10 mediates anti-inflammation and anti-fibrotic effects through negatively regulating these signaling pathways. [38][39][40][41][42][43][44] It has been shown that the treatment with IL-10 could inhibit TGF-b and NF-kB activation to reduce inflammatory response, ECM production and fibrotic genes expression in animal models of pulmonary and hepatic fibrosis. 34,45 In summary, the present study suggests that the deficiency of IL-10 aggravates inflammation and fibrosis in obstructive kidney disease.…”

Section: Interleukin-10 In Uuo Micementioning

confidence: 99%

Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model

Jin

Liu

Xie

et al. 2013

Laboratory Investigation

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“…DAMPs are derived from damaged or dying cells, and include small molecules (ATP and DNA), particles (uric acid crystals and exogenous noxious factors such as asbestos) and environmental insults such as UV irradiation 7 . Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the pathogenesis of T1DM and T2DM.Furthermore, among the vascular complications of diabetes mellitus, subclinical inflammation is also known to contribute to the pathogenesis of diabetic nephropathy 4,8,9 . In this Review we provide an update on the functional roles of Toll-like receptors (TLRs) and NOD-like receptors (NLRs) in the pathogenesis of T1DM and T2DM, and its vascular complications, namely diabetic nephropathy 10 .…”

mentioning

confidence: 99%

“…Furthermore, among the vascular complications of diabetes mellitus, subclinical inflammation is also known to contribute to the pathogenesis of diabetic nephropathy 4,8,9 . In this Review we provide an update on the functional roles of Toll-like receptors (TLRs) and NOD-like receptors (NLRs) in the pathogenesis of T1DM and T2DM, and its vascular complications, namely diabetic nephropathy 10 .…”

mentioning

confidence: 99%

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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The Inflammasomes in Kidney Disease

Cited by 305 publications

References 133 publications

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model

Innate immunity in diabetes and diabetic nephropathy

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