The microRNA-21−PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death

Ruan, Qingguo; Wang, Ting; Kameswaran, Vasumathi; Qin, Wei; Johnson, Derek; Matschinsky, Franz M.; Shi, Weiyun; Chen, Youhai H.

doi:10.1073/pnas.1101450108

Cited by 188 publications

(158 citation statements)

References 42 publications

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“…In response to a variety of stimuli, Pdcd4-null tissues and cells exhibit reduced apoptosis. 23,40 miR-21 physically interacts with an evolutionarily conserved site in the 39 untranslated region of Pdcd4 and inhibits its expression. 13,41 A subset of Pdcd4 2/2 mice spontaneously develops kidney cysts, 26 suggesting that miR-21-mediated inhibition of Pdcd4 is a plausible mechanism to aggravate cyst growth.…”

Section: Discussionmentioning

confidence: 99%

“…Programmed cell death 4 (Pdcd4) is a direct target of miR-21 and a novel tumor suppressor that promotes apoptosis. [20][21][22][23][24][25] Pdcd4 2/2 mice are born in normal Mendelian ratios and do not exhibit any overt pathology for the first few months of life. However, by approximately 80 weeks, these mice develop abdominal masses, which have been characterized as lymphoma of primary B cell origin.…”

Section: Mir-21 Promotes Survival Of Cyst Epithelial Cells Through Inmentioning

confidence: 99%

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MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Lakhia¹,

Hajarnis²,

Williams³

et al. 2015

JASN

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Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4. Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.

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Section: Discussionmentioning

confidence: 99%

Section: Mir-21 Promotes Survival Of Cyst Epithelial Cells Through Inmentioning

confidence: 99%

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Lakhia¹,

Hajarnis²,

Williams³

et al. 2015

JASN

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“…25 It has been reported that the loss of PDCD4 in macrophages attenuates NF-kB activation and promotes IL-10 production in response to LPS, thereby limiting excessive inflammation. 9 On the contrary, some other studies suggest that PDCD4 downregulation increases LPS-induced expression of proinflammatory mediators, such as TNF-a in RAW264.7 cells.…”

Section: Discussionmentioning

confidence: 99%

The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury

Wang

Zhang

Wei

et al. 2013

Laboratory Investigation

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Programmed cell death 4 (PDCD4) acts as a tumor suppressor gene, which suppresses tumor growth, infiltration and metastasis. Our previous studies demonstrated that PDCD4 had an important role in the development of ovarian cancer and glioma. Recent studies show that PDCD4 is also involved in various inflammatory diseases. However, its exact effect on inflammation remains unclear. In our current study, we explored the role of PDCD4 in acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) using wild-type (WT) mice and PDCD4-deficient mice. Our results showed that liver-to-body weight ratios, as well as serum aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly increased in PDCD4-deficient mice than WT mice. Histological examination, immunohistochemical and TUNEL analysis revealed PDCD4-deficient mice had more necrotic and apoptotic hepatocytes, inflammatory cells infiltration and liver internal hemorrhage than WT mice. In addition, some inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) in the serum and liver tissues were also significantly increased in PDCD4-deficient mice. More importantly, we found that the aggravation of liver tissue injury in PDCD4-deficient mice was due to excessive mitogen-activated protein kinase and NF-kB activation, which induced the release of more inflammatory factors, and consequently resulted in higher levels of hepatocyte necrosis and apoptosis. These results indicate that PDCD4 has a protective role in LPS/D-GalN-induced acute liver injury. This finding may present new opportunities for PDCD4 to be explored as a therapeutic target in acute liver injury.

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“…In vivo, Pdcd4 deficiency has been found to protect NOD mice against spontaneous diabetes and renders C57BL/6 mice resistant to streptozotocin (STZ)-induced diabetes. 96 Another study also performed by Roggli et al 97 showed that changes in the levels of the miR-29 family contributed to the β-cell dysfunction induced by proinflammatory cytokines during the initial phases of T1D. miR-29a/b/c is upregulated in islets isolated from NOD mice during the phases preceding diabetes manifestation.…”

Section: Mirnas: Participants In Autoimmunity-mediated β-Cell Damagementioning

confidence: 99%

“…C-Rel and p65 are important members of the NF-κB family. In β-cells, they can activate the promoter of the miR-21 gene, thereby upregulating miR-21 expression; miR-21 sequentially inhibits Pdcd4 expression, 96 which is involved in the progression to cell death. Previous studies have shown that Pdcd4-deficient β-cells are resistant to death.…”

Section: Mirnas: Participants In Autoimmunity-mediated β-Cell Damagementioning

confidence: 99%

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

2017

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MicroRNAs (miRNAs) are a series of conserved, short, non-coding RNAs that modulate gene expression in a posttranscriptional manner. miRNAs are involved in almost every physiological and pathological process. Type 1 diabetes (T1D) is an autoimmune disease that is the result of selective destruction of pancreatic β-cells driven by the immune system. miRNAs are also important participants in T1D pathogenesis. Herein, we review the most recent data on the potential involvement of miRNAs in T1D. Specifically, we focus on two aspects: the roles of miRNAs in maintaining immune homeostasis and regulating β-cell survival and/or functions in T1D. We also discuss circulating miRNAs as potent biomarkers for the diagnosis and prediction of T1D and investigate potential therapeutic approaches for this disease.

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The microRNA-21−PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death

Cited by 188 publications

References 42 publications

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

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