Deletion of Smad3 prevents renal fibrosis and inflammation in type 2 diabetic nephropathy

Xu, Bihua; Sheng, Jingyi; You, Yong‐Ke; Huang, Xiao‐Ru; Ma, Rong; Wang, Qingwen; Lan, Hui‐Yao

doi:10.1016/j.metabol.2019.154013

Cited by 80 publications

(88 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…18,19 Another research found that knockout of Smad3 suppressed inflammation and fibrosis in the kidney of db/db mice. 20 These previous findings indicate that the TGF-β1/Smad3 pathway is a potential target for the treatment of renal fibrosis in DN.…”

Section: Introductionmentioning

confidence: 83%

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

Zheng¹,

Zhu²,

Lei³

et al. 2020

DDDT

View full text Add to dashboard Cite

Introduction: Diabetic nephropathy (DN) has become an increasing threat to health, and inflammation and fibrosis play important roles in its progression. Wogonin, a flavonoid, has been proven to suppress inflammation and fibrosis in various diseases, including acute kidney injury. This study aimed at investigating the effect of wogonin on diabetes-induced renal inflammation and fibrosis. Materials and Methods: Streptozotocin (STZ)-induced diabetic mouse models received gavage doses of wogonin (10, 20, and 40 mg/kg) for 12 weeks. Metabolic indices from blood and urine and pathological damage of glomerulus in the diabetic model were assessed. Glomerular mesangial cells SV40 were cultured in high glucose (HG) medium containing wogonin at concentrations of 1.5825, 3.125, and 6.25 μg/mL for 24 h. Inflammation and fibrosis indices were evaluated by histopathological, Western blotting, and PCR analyses. Results: Wogonin treatment ameliorated albuminuria and histopathological lesions in diabetic mice. Inflammatory cytokines, such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and related signaling pathway NF-κB were downregulated after the administration of wogonin in vivo and in vitro. Furthermore, wogonin reduced the expression of extracellular matrix (ECM), including fibronectin (FN), collagen IV (Col-IV), α-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1) in the kidneys of diabetic mice and HG-induced mesangial cells. Moreover, the inhibition of TGF-β1/Smad3 pathway might be responsible for these changes. Conclusion: Wogonin may ameliorate renal inflammation and fibrosis in diabetic nephropathy by inhibiting the NF-κB and TGF-β1/Smad3 signaling pathways.

show abstract

Section: Introductionmentioning

confidence: 83%

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

Zheng¹,

Zhu²,

Lei³

et al. 2020

DDDT

View full text Add to dashboard Cite

show abstract

“…Recent study showed that complete deletion of Smad3 in db/db mouse significantly reduced urinary albumin excretion, serum creatinine, mesangial matrix accumulation, and GBM thickness. As shown by immunohistochemistry, the deposition, expression, and transcription of collagen I and IV were significantly inhibited ( Xu et al, 2020 ).…”

Section: The Role Of Lrg1 In Abnormal Angiogenesis Of Dnmentioning

confidence: 99%

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

et al. 2020

View full text Add to dashboard Cite

Diabetic nephropathy (DN) is an important public health concern of increasing proportions and the leading cause of end-stage renal disease (ESRD) in diabetic patients. It is one of the most common long-term microvascular complications of diabetes mellitus that is characterized by proteinuria and glomerular structural changes. Angiogenesis has long been considered to contribute to the pathogenesis of DN, whereas the molecular mechanisms of which are barely known. Angiogenic factors associated with angiogenesis are the major candidates to explain the microvascular and pathologic finds of DN. Vascular endothelial growth factor A (VEGF-A), leucine-rich α-2-glycoprotein 1, angiopoietins and vasohibin family signal between the podocytes, endothelium, and mesangium have important roles in the maintenance of renal functions. An appropriate amount of VEGF-A is beneficial to maintaining glomerular structure, while excessive VEGF-A can lead to abnormal angiogenesis. LRG1 is a novel pro-angiogenic factors involved in the abnormal angiogenesis and renal fibrosis in DN. The imbalance of Ang1/Ang2 ratio has a role in leading to glomerular disease. Vasohibin-2 is recently shown to be in diabetes-induced glomerular alterations. This review will focus on current understanding of these angiogenic factors in angiogenesis and pathogenesis associated with the development of DN, with the aim of evaluating the potential of anti-angiogenesis therapy in patients with DN.

show abstract

“…Long non‐coding RNAs (lncRNAs), defined as RNAs >200 nt in length that lack protein‐coding capability, participate in the renal fibrosis process in DN 10‐12 . By using the Arraystar human lncRNA/mRNA expression profile microarray (v3.0), we previously reported 21 up‐regulated lncRNAs, including the lncRNAs ARAP1‐AS2, and 726 up‐regulated mRNAs, including the mRNAs ARAP1 in the sera of DN patients compared with that of healthy controls 13 .…”

Section: Introductionmentioning

confidence: 99%

LncRNA ARAP1‐AS2 promotes high glucose‐induced human proximal tubular cell injury via persistent transactivation of the EGFR by interacting with ARAP1

Tian

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

The persistent transactivation of epidermal growth factor receptor (EGFR) causes subsequent activation of the TGF‐β/Smad3 pathway, which is closely associated with fibrosis and cell proliferation in diabetic nephropathy (DN), but the exact mechanism of persistent EGFR transactivation in DN remains unclear. ARAP1, a susceptibility gene for type 2 diabetes, can regulate the endocytosis and ubiquitination of membrane receptors, but the effect of ARAP1 and its natural antisense long non‐coding RNA (lncRNA), ARAP1‐AS2, on the ubiquitination of EGFR in DN is not clear. In this study, we verified that the expression of ARAP1 and ARAP1‐AS2 was significantly up‐regulated in high glucose‐induced human proximal tubular epithelial cells (HK‐2 cells). Moreover, we found that overexpression or knockdown of ARAP1‐AS2 could regulate fibrosis and HK‐2 cell proliferation through EGFR/TGF‐β/Smad3 signalling. RNA pulldown assays revealed that ARAP1‐AS2 directly interacts with ARAP1. Coimmunoprecipitation, dual‐immunofluorescence and ubiquitination assays showed that ARAP1 may maintain persistent EGFR activation by reducing EGFR ubiquitination through competing with Cbl for CIN85 binding. Taken together, our results suggest that the lncRNA ARAP1‐AS2 may promote high glucose‐induced proximal tubular cell injury via persistent EGFR/TGF‐β/Smad3 pathway activation by interacting with ARAP1.

show abstract

Deletion of Smad3 prevents renal fibrosis and inflammation in type 2 diabetic nephropathy

Cited by 80 publications

References 41 publications

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

<p>Wogonin Ameliorates Renal Inflammation and Fibrosis by Inhibiting NF-κB and TGF-β1/Smad3 Signaling Pathways in Diabetic Nephropathy</p>

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

LncRNA ARAP1‐AS2 promotes high glucose‐induced human proximal tubular cell injury via persistent transactivation of the EGFR by interacting with ARAP1

Contact Info

Product

Resources

About