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Abstract: PO0655

LRG1 Promotes Renal Fibrosis by Enhancing TGF-β-Induced Smad3 Pathway

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms


  • Hong, Quan, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Cai, Hong, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Zhang, Lu, Icahn School of Medicine at Mount Sinai, New York, United States
  • Ni, Zhaohui, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, Shanghai, China
  • Cai, Guangyan, Chinese PLA General Hospital, Beijing, Beijing, China
  • Chen, Xiangmei, Chinese PLA General Hospital, Beijing, Beijing, China
  • He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Renal fibrosis is a final convergent pathway for CKD progression, but effective fibrosis therapy is lacking. We recently showed that leucine-rich alpha-2 glycoprotein-1 (LRG1), a secreted glycoprotein, is highly upregulated in diabetic kidneys and potentiated the endothelial TGF-β signaling, mediated by ALK1 receptor and Smad1/5 activation, to increase angiogenesis and worsen DKD progression. However, increased LRG1 expression was not limited to the endothelial cells in the diabetic kidneys, but also found in the renal tubular epithelial cells (RTECs). Therefore, we examined whether LRG1 contributes to the TGF-β signaling in RTECs leading to renal fibrosis progression.


We examined the expression of LRG1 in the tubulointerstitium RNAseq datasets of human CKD. We explored the potential mechanism in LRG1 upregulation in cultured RTECs and examined the specific TGF-β/Smad signaling pathway mediated by LRG1 using shRNA-knockdown. We examined the effects of global Lrg1 ablation in unilateral ureteral obstruction (UUO) and aristolochic acid nephropathy (AAN) models of renal fibrosis. We also examined the effects of RTEC-specific overexpression of LRG1 in renal fibrosis in vivo. We further compared the activation of Smad proteins in the RTECs of control, Lrg1-/-, and Pax8-LRG1OE mice with UUO.


We found that the LRG1 mRNA transcript was markedly increased in the microdissected tubulointerstitium of human CKD. In cultured RTECs, LRG1 expression was upregulated by a pro-inflammatory cytokine TNF-α, and chromatin IP assay confirmed the binding of p65 subunit NF-κB to the LRG1 promoter region. Importantly, LRG1 enhanced the TGF-β-induced Smad3 activation, but not of Smad1/5, and the expression of pro-fibrotic genes in RTECs. The global knockout of Lrg1 attenuated renal fibrosis in mice with UUO or AAN. In AAN mice, Lrg1 ablation also improved renal function. In contrast, the RTEC-specific overexpression of LRG1 markedly heightened the renal fibrosis in vivo. The level of Smad3 phosphorylation in RTECs in the obstructed kidneys was directly associated with the loss or gain of LRG1 expression.


Our current study attributes a previously undescribed role of LRG1 as a key modulator of the canonical TGF-β/Smad3 signal transduction in RTECs and suggests that the targeting of LRG1 may be an effective approach against renal fibrosis.


  • NIDDK Support