Identification of NOD2 as a novel target of RNA-binding protein HuR: evidence from NADPH oxidase-mediated HuR signaling in diabetic nephropathy

Shang, Jin; Wan, Qiang; Wang, Xiaojie; Duan, Yiqi; Wang, Ziying; Wei, Xinbing; Zhang, Yan; Wang, Hui; Wang, Rong

doi:10.1016/j.freeradbiomed.2014.12.013

Cited by 43 publications

(43 citation statements)

References 41 publications

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“…RNA-binding protein human antigen (HuR) is upregulated in patients with diabetic nephropathy, and correlates with the degree of proteinuria 155 . In vitro experiments using rat glomerular mesangial cells have indicated that high glucose can induce a prominent increase in cytoplasmic HuR, which allows HuR to bind to the 3'-untranslated region of NOD2 and enhance the expression of NOD2 and mRNA stability 155 .…”

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

confidence: 99%

“…In vitro experiments using rat glomerular mesangial cells have indicated that high glucose can induce a prominent increase in cytoplasmic HuR, which allows HuR to bind to the 3'-untranslated region of NOD2 and enhance the expression of NOD2 and mRNA stability 155 . NOD1 and NOD2 were initially implicated in the pathogenesis of AKI by canonical signaling events, where tissue necrosis produces endogenous agonists to stimulate NODs and converge into the activation of proinflammatory responses 131 .…”

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

confidence: 99%

“…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 .RNA-binding protein human antigen (HuR) is upregulated in patients with diabetic nephropathy, and correlates with the degree of proteinuria 155 . In vitro experiments using rat glomerular mesangial cells have indicated that high glucose can induce a prominent increase in cytoplasmic HuR, which allows HuR to bind to the 3'-untranslated region of NOD2 and enhance the expression of NOD2 and mRNA stability 155 .…”

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confidence: 99%

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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: 99%

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

confidence: 99%

mentioning

confidence: 99%

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Innate immunity in diabetes and diabetic nephropathy

2015

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“…These results provided direct evidence on the contribution of NOD2 canonical and non-canonical effects in diabetic nephropathy [44]. Furthermore, we found that human antigen R (HuR), a RNA-binding protein which regulates mRNA cargos that contain adenylate-uridylate-rich elements (AREs) in the 3′-untranslated region [45], contributed to NOD2 mRNA stability in diabetic nephropathy [46]. Among four AUUUA regions (ARE1-4) of the 3′-untranslated region of NOD2, HuR can directly bind to ARE4 of NOD2 to enhance NOD2 mRNA stability and expression.…”

Section: Nlrs and Ckdmentioning

confidence: 99%

“…NOX4 is an important subunit of NADPH oxidase to produce renal reactive oxygen species (ROS) and deficiency of NOX4 results in renal protection from glomerular injury in diabetic mice [49,50]. We further found that NOX4-mediated redox signaling contributed to the expression and translocation of HuR and NOD2 mRNA stability [46]. …”

Section: Nlrs and Ckdmentioning

confidence: 99%

The Nucleotide Oligomerization Domain-Like Receptors in Kidney Injury

Wang

2016

Kidney Dis

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Background: Inflammation is a hallmark of almost all forms of renal injury and the activation of the innate immune system is of importance in the development of many kidney diseases. Pattern recognition receptors (PRRs) act as sensors of the innate immune system to detect pathogen- or damage-associated molecular patterns, which initiate immune responses to resolve infections and repair damaged tissues. Abnormalities in PRR activation will lead to excessive inflammation. Summary: Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are recently identified intracellular PRRs that are essential to innate immune responses and tissue homeostasis. A better understanding of the function of NLRs will provide unexpected opportunities to develop new therapies for kidney diseases by modulation of the innate immune system. Key Messages: NLRs are constitutively expressed in the kidney and emerging evidence has shown that activation of NLRs plays an important role in the pathogenesis of renal injury. Among NLRs, NOD2 and NLRP3 inflammasome are the best characterized members in the kidney. In this review, we summarize current knowledge about the pathological mechanisms that are related to NOD2 and NLRP3 inflammasome in various kidney diseases by their canonical and non-canonical effects and discuss the opportunities of pharmacological targeting of NLR-mediated signaling pathways at multiple levels for the treatment of renal disease.

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ANKRD1 aggravates renal ischaemia‒reperfusion injury via promoting TRIM25‐mediated ubiquitination of ACSL3

Han,

Guo,

Kong

et al. 2024

Clinical & Translational Med

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BackgroundRenal ischaemia‒reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI). To date, effective therapies for delaying renal IRI and postponing patient survival remain absent. Ankyrin repeat domain 1 (ANKRD1) has been implicated in some pathophysiologic processes, but its role in renal IRI has not been explored.MethodsThe mouse model of IRI‐AKI and in vitro model were utilised to investigate the role of ANKRD1. Immunoprecipitation‐mass spectrometry was performed to identify potential ANKRD1‐interacting proteins. Protein‒protein interactions and protein ubiquitination were examined using immunoprecipitation and proximity ligation assay and immunoblotting, respectively. Cell viability, damage and lipid peroxidation were evaluated using biochemical and cellular techniques.ResultsFirst, we unveiled that ANKRD1 were significantly elevated in renal IRI models. Global knockdown of ANKRD1 in all cell types of mouse kidney by recombinant adeno‐associated virus (rAAV9)‐mitigated ischaemia/reperfusion‐induced renal damage and failure. Silencing ANKRD1 enhanced cell viability and alleviated cell damage in human renal proximal tubule cells exposed to hypoxia reoxygenation or hydrogen peroxide, while ANKRD1 overexpression had the opposite effect. Second, we discovered that ANKRD1's detrimental function during renal IRI involves promoting lipid peroxidation and ferroptosis by directly binding to and decreasing levels of acyl‐coenzyme A synthetase long‐chain family member 3 (ACSL3), a key protein in lipid metabolism. Furthermore, attenuating ACSL3 in vivo through pharmaceutical approach and in vitro via RNA interference mitigated the anti‐ferroptotic effect of ANKRD1 knockdown. Finally, we showed ANKRD1 facilitated post‐translational degradation of ACSL3 by modulating E3 ligase tripartite motif containing 25 (TRIM25) to catalyse K63‐linked ubiquitination of ACSL3, thereby amplifying lipid peroxidation and ferroptosis, exacerbating renal injury.ConclusionsOur study revealed a previously unknown function of ANKRD1 in renal IRI. By driving ACSL3 ubiquitination and degradation, ANKRD1 aggravates ferroptosis and ultimately exacerbates IRI‐AKI, underlining ANKRD1's potential as a therapeutic target for kidney IRI.Key Points/Highlights Ankyrin repeat domain 1 (ANKRD1) is rapidly activated in renal ischaemia‒reperfusion injury (IRI) models in vivo and in vitro. ANKRD1 knockdown mitigates kidney damage and preserves renal function. Ferroptosis contributes to the deteriorating function of ANKRD1 in renal IRI. ANKRD1 promotes acyl‐coenzyme A synthetase long‐chain family member 3 (ACSL3) degradation via the ubiquitin‒proteasome pathway. The E3 ligase tripartite motif containing 25 (TRIM25) is responsible for ANKRD1‐mediated ubiquitination of ACSL3.

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Identification of NOD2 as a novel target of RNA-binding protein HuR: evidence from NADPH oxidase-mediated HuR signaling in diabetic nephropathy

Cited by 43 publications

References 41 publications

Innate immunity in diabetes and diabetic nephropathy

Innate immunity in diabetes and diabetic nephropathy

The Nucleotide Oligomerization Domain-Like Receptors in Kidney Injury

ANKRD1 aggravates renal ischaemia‒reperfusion injury via promoting TRIM25‐mediated ubiquitination of ACSL3

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