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Abstract: TH-PO960

Tenascin-C-Rich Extracellular Microenvironment Impairs Renal Tubular Integrity and Promotes Renal Fibrosis

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic


  • Zhu, Haili, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Liao, Jinlin, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Hong, Xue, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Fu, Haiyan, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Tenascin-C (TNC), an extracellular matrix glycoprotein, is the major component of fibrogenic niche that facilitates renal fibrosis through multiple mechanisms. We previously reported that focal expression of TNC after injury sets up a favorable microenvironment for fibroblast activation and proliferation. However, whether such a TNC-rich niche also affects tubular cell integrity and phenotype remains unclear.


Serum and biopsy specimens from CKD patients as well as various CKD animal models were used. TNC and its downstream signaling was manipulated or therapeutically inhibited in vivo. The 2-Dimensional and 3-Dimensional culture of human kidney proximal tubular cells (HKC-8) and mouse primary proximal tubular epithelial cells were applied.


ELISA results demonstrated that TNC level significantly elevated in the serum of CKD patients, and consistently its expression was also induced in kidney biopsy specimens from CKD patients with different etiologies. In vitro, TNC significantly promoted HKC-8 cell migration and induced them to undergo epithelial-mesenchymal transition (EMT). Similarly, TNC also impaired the integrity of mouse primary proximal tubular epithelial cells by triggering EMT. Using de-cellularized kidney tissue scaffold (KTS) isolated from fibrotic kidneys, we found that TNC-enriched KTS facilitated tubular epithelial cell EMT, whereas TNC-deprived KTS inhibited it. Mechanistically, TNC induced integrin αvβ6, activated focal adhesion kinase (FAK), leading to the activation of ERK signaling. Blockade of FAK signaling abolished TNC’s ability to induce tubular cell EMT in vitro. In mouse models of CKD induced by unilateral ureteral obstruction or ischemia/reperfusion injury, knockdown TNC or specific inhibition of FAK signaling with small molecule inhibitor repressed partial EMT and ameliorated fibrotic lesions.


These studies unveil that TNC-rich extracellular niche plays a critical role in impairing tubular cell integrity by inducing partial EMT. Our data also indicate that blockade of TNC/FAK signaling is a novel strategy for therapeutic intervention of renal fibrosis.


  • NIDDK Support