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Abstract: SA-PO231

Long Non-Coding RNA DANCR Synergizes With IGF2BP2 to Attenuate Diabetic Kidney Disease Induced Glomerulosclerosis by Negatively Regulating the TGF-β/Smad3 Pathway

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Liu, Feng, Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • Zhang, Chun, Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and the leading cause of end-stage kidney disease. Despite transforming growth factor-β (TGF-β) has been implicated as a major pathogenic factor in the development of glomerulosclerosis in DKD, clinical trials with monoclonal antibodies to TGF-β have failed to demonstrate therapeutic benefit. Thus, developing alternative therapeutic strategies to effectively block the TGF-β/Smad signaling could be of paramount importance for the treatment of DKD. To date, whether lncRNAs can regulate the TGF-β/SMAD signaling in the development of DKD-associated glomerulosclerosis is still unknown.

Methods

Through integrating analysis of a public RNA sequencing dataset of 61 DKD glomerular cases, RNA fluorescence in situ hybridization, RNA pulldown assay, and mass spectrometry analysis, DANCR was identified and its interaction with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was confirmed. Biological implications of DANCR and IGF2BP2 in human renal mesangial cells (HRMCs) under high glucose (HG) or TGF-β stimulus were explored by flow cytometry and western blot analysis. Weighted gene co-expression network analysis and real-time quantitative RT-PCR (qRT-PCR) verification were performed to identify candidate target genes for DANCR in DKD. RNA immunoprecipitation (RIP), dual-luciferase assay, qRT-PCR and western blot assays were used to investigate the molecular mechanisms underlying the functions of DANCR and IGF2BP2.

Results

DANCR was predominantly detected in the cytoplasm, and was downregulated in DKD glomerular tissues and HG stimulated HRMCs. Ectopic expression of DANCR abolished the synthesis of fibronectin, Col I, and α-SMA induced by the HG or TGF-β1 stimulation and restored the expression of NLK. Mechanistically, DANCR functioned to stabilize nemo-like kinase (NLK) mRNA through interaction with IGF2BP2, resulting in enhanced phosphorylating on the linker region of activated Smad2/3 that blocked TGF-β/Smad signaling.

Conclusion

This study identifies long non-coding RNA DANCR as a new TGF-β/Smad signaling blocker that inhibits the development of glomerulosclerosis in DKD through interacting with IGF2BP2 to stabilize NLK mRNA, indicating a potential therapeutic target for treatment of glomerulosclerosis in DKD.