Decreased DANCR contributes to high glucose‐induced extracellular matrix accumulation in human renal mesangial cell via regulating the TGF‐β/Smad signaling. Issue 5 (13th April 2023)

• Record Type: Journal Article
• Authors: Liu, Feng; Cao, Yiling; Zhang, Chun; Su, Hua
• Is Part Of: FASEB journal. Volume 37:Issue 5(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-04-13
• Subjects: DANCR -- diabetic kidney diseases -- human renal mesangial cell -- IGF2BP2 -- NLK -- TGF‐β; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202300146R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Glomerulosclerosis is one of the major histopathologic changes in diabetic kidney diseases (DKD), which is characterized by excessive deposition of extracellular matrix (ECM) in the glomerulus mainly produced by mesangial cells in response to transforming growth factor‐β (TGF‐β) stimuli under diabetic conditions. Despite TGF‐β has been implicated as a major pathogenic factor in the development of diabetic glomerulosclerosis, clinical trials of monoclonal antibodies against TGF‐β failed to demonstrate therapeutic benefits. Thus, developing alternative therapeutic strategies to effectively block the TGF‐β/Smad signaling could be of paramount importance for DKD treatment. Emerging evidence indicates that dysregulation of certain lncRNAs can lead to aberrant activation of TGF‐β/Smad signaling. Herein, we identified a novel lncRNA, named DANCR, which could efficiently function as a negative regulator of TGF‐β/Smad signaling in mesangial cells. Ectopic expression of DANCR could specifically block the activation of TGF‐β/Smad signaling induced by high‐glucose or TGF‐β in human renal mesangial cells (HRMCs). Mechanistically, DANCR functions to stabilize nemo‐like kinase (NLK) mRNA through interaction with insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2), resulting in enhanced phosphorylating on the linker region of activated Smad2/3 in the nucleus. Taken together, our data have uncovered an lncRNA‐based regulatory modality of the TGF‐β/Smad signaling and identified DANCR as an endogenous blocker of TGF‐β/Smad signaling in HRMCs, which may represent a potential therapeutic target against the diabetic glomerulosclerosis. Abstract : Schematic illustration of decreased DANCR contributes to high glucose‐induced extracellular matrix accumulation in human renal mesangial cell (HRMC) by relieving the inhibitory effect of NLK in the TGF‐β/Smad signaling pathway. Specifically, DANCR blocks the TGF‐β/Smad signaling pathway and attenuates the deposition of ECM proteins in HRMC by recruiting IGF2BP2 protein to stabilize NLK mRNA and thus enhances activated Smad2/3 phosphorylation and degradation in the nucleus.