Smad3 deficiency promotes beta cell proliferation and function in <i>db/db</i> mice <i>via</i> restoring Pax6 expression

Sheng, Jingyi; Wang, Li; Tang, Patrick Ming‐Kuen; Wang, Hong‐Lian; Li, Jianchun; Xu, Bihua; Xue, Vivian Weiwen; Tan, Ruizhi; Jin, Nana; Chan, Ting‐Fung; Huang, Xiao‐Ru; Ma, Rong; Lan, Hui‐Yao

doi:10.7150/thno.51857

Cited by 22 publications

(48 citation statements)

References 40 publications

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“…In view of DN, mice null for Smad3 are protected from renal fibrosis including GBM thickening and ECM overproduction in STZ-induced DN [74], although inhibition of albuminuria is always observed [75]. In type 2 diabetes-associated DN, our study reveals that deletion of Smad3 from db/db mice prevents the development of DN as Smad3KO-db/db mice are free from diabetes and DN with normal levels of blood glucose and serum creatinine without insulin resistance, glucose intolerance, obesity, albuminuria, and renal pathology [76,77]. All these findings demonstrate an essential role for Smad3 in the pathogenesis of DN in both type 1 and type 2 diabetes.…”

Section: Smad3 Vs Smad2mentioning

confidence: 67%

“…As Smad3, but not Smad2, plays a critical role in the pathogenesis of diabetes and DN [76,77], targeting Smad3 represents a novel and effective strategy for the treatment of DN. In the UUO mouse model, inhibition of Smad3 with specific inhibitor of Smad3 (SIS3) attenuates renal fibrosis and inflammation [143,144].…”

Section: Treatment Of Dn By Targeting Tgf-β Signalingmentioning

confidence: 99%

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TGF-Beta as a Master Regulator of Diabetic Nephropathy

Wang

Liu

et al. 2021

IJMS

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Diabetic nephropathy (DN) is one of the most common complications in diabetes mellitus and the leading cause of end-stage renal disease. TGF-β is a pleiotropic cytokine and has been recognized as a key mediator of DN. However, anti-TGF-β treatment for DN remains controversial due to the diverse role of TGF-β1 in DN. Thus, understanding the regulatory role and mechanisms of TGF-β in the pathogenesis of DN is the initial step towards the development of anti-TGF-β treatment for DN. In this review, we first discuss the diverse roles and signaling mechanisms of TGF-β in DN by focusing on the latent versus active TGF-β1, the TGF-β receptors, and the downstream individual Smad signaling molecules including Smad2, Smad3, Smad4, and Smad7. Then, we dissect the regulatory mechanisms of TGF-β/Smad signaling in the development of DN by emphasizing Smad-dependent non-coding RNAs including microRNAs and long-non-coding RNAs. Finally, the potential therapeutic strategies for DN by targeting TGF-β signaling with various therapeutic approaches are discussed.

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Section: Smad3 Vs Smad2mentioning

confidence: 67%

Section: Treatment Of Dn By Targeting Tgf-β Signalingmentioning

confidence: 99%

TGF-Beta as a Master Regulator of Diabetic Nephropathy

Wang

Liu

et al. 2021

IJMS

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“…To uncover the downstream mechanism of Smad3 in regulating β cell proliferation, we performed RNA-seq in islets isolated from db/m or db/db mice with or without deletion of Smad3 gene including Smad3WT-db/db, Smad3KO-db/db, Smad3WT-db/m, and Smad3KO-db/m mice as previously described 9 . Pathway enrichment analysis was conducted among the differentially expressed genes (DEGs) between Smad3WT and Smad3KO islets in db/m or db/db background.…”

Section: Resultsmentioning

confidence: 99%

“…Our recent work also found that deletion of Smad3 in db/db mice (Smad3KO-db/db) prevents the onset of overt diabetes without obesity, hyperglycemia, insulin resistance, and glucose intolerance. Interestingly, Smad3KO-db/db mice show islet hyperplasia with significantly increased β cell proliferation and persistent hyperinsulinemia 9 . This implies that Smad3 is pathogenic in diabetes and targeting Smad3 in β cells may represent a novel β cell or islet replacement therapy for diabetes.…”

Section: Introductionmentioning

confidence: 99%

Smad3 deficiency improves islet-based therapy for diabetes and diabetic kidney injury by promoting β cell proliferation via the E2F3-dependent mechanism

Wang¹,

Wei²,

He³

et al. 2022

Theranostics

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Rationale: Poor β cell proliferation is one of the detrimental factors hindering islet cell replacement therapy for patients with diabetes. Smad3 is an important transcriptional factor of TGF-β signaling and has been shown to promote diabetes by inhibiting β cell proliferation. Therefore, we hypothesize that Smad3-deficient islets may be a novel cell replacement therapy for diabetes. Methods: We examined this hypothesis in streptozocin-induced type-1 diabetic mice and type-2 diabetic db/db mice by transplanting Smad3 knockout (KO) and wild type (WT) islets under the renal capsule, respectively. The effects of Smad3KO versus WT islet replacement therapy on diabetes and diabetic kidney injury were examined. In addition, RNA-seq was applied to identify the downstream target gene underlying Smad3-regulated β cell proliferation in Smad3KO-db/db versus Smad3WT-db/db mouse islets. Results: Compared to Smad3WT islet therapy, treatment with Smad3KO islets produced a much better therapeutic effect on both type-1 and type-2 diabetes by significantly lowering serum levels of blood glucose and HbA1c and protected against diabetic kidney injuries by preventing an increase in serum creatinine and the development of proteinuria, mesangial matrix expansion, and fibrosis. These were associated with a significant increase in grafted β cell proliferation and blood insulin levels, resulting in improved glucose intolerance. Mechanistically, RNA-seq revealed that compared with Smad3WT-db/db mouse islets, deletion of Smad3 from db/db mouse islets markedly upregulated E2F3 , a pivotal regulator of cell cycle G1/S entry. Further studies found that Smad3 could bind to the promoter of E2F3 , and thus inhibit β cell proliferation via an E2F3-dependent mechanism as silencing E2F3 abrogated the proliferative effect on Smad3KO β cells. Conclusion: Smad3-deficient islet replacement therapy can significantly improve both type-1 and type-2 diabetes and protect against diabetic kidney injury, which is mediated by a novel mechanism of E2F3-dependent β cell proliferation.

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“…SMAD3 deficiency prevents renal inflammation and fibrosis in SMAD3-db/db mice via regulations of lncRNA Erbb4-IR.transcription and miR-29b ( Xu et al, 2020a ). SMAD3 deficiency protects against diabetes-associated beta cell dysfunction and loss in DN mice ( Sheng et al, 2021 ). SMAD3 also promotes autophagy dysregulation and kidney injury ( Yang et al, 2020 ).…”

Section: Inflammation In the Progression Of Dnmentioning

confidence: 99%

Epigenetics and Inflammation in Diabetic Nephropathy

Shao

Zhang

et al. 2021

Front. Physiol.

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Diabetic nephropathy (DN) leads to high morbidity and disability. Inflammation plays a critical role in the pathogenesis of DN, which involves renal cells and immune cells, the microenvironment, as well as extrinsic factors, such as hyperglycemia, chemokines, cytokines, and growth factors. Epigenetic modifications usually regulate gene expression via DNA methylation, histone modification, and non-coding RNAs without altering the DNA sequence. During the past years, numerous studies have been published to reveal the mechanisms of epigenetic modifications that regulate inflammation in DN. This review aimed to summarize the latest evidence on the interplay of epigenetics and inflammation in DN, and highlight the potential targets for treatment and diagnosis of DN.

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Smad3 deficiency promotes beta cell proliferation and function in db/db mice via restoring Pax6 expression

Cited by 22 publications

References 40 publications

TGF-Beta as a Master Regulator of Diabetic Nephropathy

TGF-Beta as a Master Regulator of Diabetic Nephropathy

Smad3 deficiency improves islet-based therapy for diabetes and diabetic kidney injury by promoting β cell proliferation via the E2F3-dependent mechanism

Epigenetics and Inflammation in Diabetic Nephropathy

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