Abstract: FR-PO389
Latent Transforming Growth Factor Beta Biding Protein 4 (LTBP4) Attenuates Tubulointerstitial Fibrosis and Ameliorates Inflammation and Mitochondrial Dysfunction in CKD
Session Information
- CKD: Mechanisms - II
November 08, 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
- Su, Chi-Ting, Univeristy of Pittsburgh, Pittsuburgh, United States
- Jao, Tzu-Ming, National Taiwan University, Taipei, Taiwan
- Huang, Jenq-wen, National Taiwan University, Taipei, Taiwan
- Urban, Zsolt, Univeristy of Pittsburgh, Pittsuburgh, Pennsylvania, United States
Background
Transforming growth factor beta (TGFβ) has been well known as a key factor for fibrosis and inflammation. LTBPs regulate TGFβ signaling in complicated ways. Disruption and loss of LTBP4 expression is associated with abnormal accumulation of extra-cellular matrix (ECM) and altered TGFβ activation. However, the role of LTBP4 in chronic kidney disease remains largely unknown.
Methods
To investigate the impact of LTBP4 on tubulointeresitial fibrosis (TIF), we generated LTBP4-overexpression and LTBP4-deficiency human renal proximal tubule cells (HK-2), treated with exogenous TGFbeta and established a fibroblasts-HK-2 co-culture system using rat fibroblasts (NRK-49F) and HK-2 cells. Moreover, to create TIF model, we performed unilateral ureteral ligation (UUO) in Ltbp4S-/- mice and wild-type (WT) mice to check ECM deposition and phenotypic alterations.
Results
Up-regulation of Ltbp4 in fibrotic kidney was noted in TIF model with UUO. Markers and mediators of fibrosis, α-SMA, fibronectin, collagen I, Pdgfrβ and TGFβ in gene and protein levels were reduced significantly in LTBP4-knock down HK-2 cells treated with additional TGFbeta. LTBP4-overexpression enhanced epithelial-mesenchymal transition (EMT) with showing decreased epithelial-cadherin, increased vimentin and collagen I in the co-culture system. In addition, lower expression of Pdgfrβ with higher expression of Nrf2 signaling was noted in fibrotic kidneys in Ltbp4S-/- mice compared with changes in WT mice, suggesting inflammation condition could be altered by the absence of Ltbp4S. Ltbp4-deficiency also reduced inflammatory gene expression such as IL-6 and altered IL-6-associated mitochondrial biogenesis.
Conclusion
Ltbp4 acts as a regulator of fibrosis and inflammation. Ltbp4 appears to inhibit antioxidant Nrf2 pathway and enhance fibrosis in a TGFβ-related manner in a murine UUO model of TIF and in a cell co-culture system. In addition, LTBP4 deficiency ameliorates mitochondrial dysfunction and alleviates renal fibrosis.