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Kidney Week

Abstract: TH-PO490

TGFBI and Kidney Disease Progression

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Ebefors, Kerstin, University of Gothenburg, Goteborg, Sweden
  • Walter, Debra L., University of Michigan, Ann Arbor, Michigan, United States
  • Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
  • Cederblad, Linda, AstraZeneca, Mölndal, Sweden
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Menon, Rajasree, University of Michigan, Ann Arbor, Michigan, United States
  • Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States
  • Eketjäll, Susanna, AstraZeneca, Mölndal, Sweden
  • Reznichenko, Anna, AstraZeneca, Mölndal, Sweden
  • Nystrom, Jenny C., University of Gothenburg, Goteborg, Sweden
  • Bitzer, Markus, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Williams, Julie, AstraZeneca, Mölndal, Sweden
Background

TGFBI was identified as one of the genes whose hypomethylation is associated with chronic kidney disease (CKD) progression. Increased expression of TGFBI is reported in patients with diabetic kidney disease (DKD) and was considered to play a central role in a novel pathway that promotes DKD. However, the molecular mechanism of TGFBI in kidney disease progression remains to be determined.

Methods

Bioinformatic analysis was performed to investigate the association of TGFBI expression with kidney disease association in human and mouse models for kidney disease. Single cell RNAseq analysis, in situ hybridization and IHC were used to determine the cellular localization. Expression of key pathway genes was evaluated in TGFBI treated-human mesangial and podocyte cells by qRT-PCR and IHC.

Results

Higher expression of TGFBI is associated with increased kidney disease severity in transforming growth factor-β1 transgenic mice (Albumin/Tgfb1 Tg), developing focal segmental glomerular sclerosis and tubulointerstitial injury. In patients with various CKD etiologies, TGFBI expression is reversely correlated with glomerular filtration rate (GFR), including DKD and SLE. Single cell RNAseq analysis demonstrated that TGFBI is enriched in immune cells, followed by mesangial cells. In vitro mesangial cells can produce TGFBI and knock down reduces pathogenic proliferation. Treatment of podocytes with TGFBI leads to actin cytoskeletal rearrangement and fibrotic gene expression, suggesting that increased Tgfbi expression by mesangial cells may cause the podocyte injury. This is supported by the observation that Tgfbi mRNA is reversely associated with podocyte density (r=-0.66, p<0.01) in Tgfb1 Tg mice.

Conclusion

TGFBI is an important player in CKD/DKD progression by initiating podocyte injury which will lead to proteinuria.

Funding

  • Commercial Support