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Kidney Week

Abstract: FR-PO337

Pathologic Cross-Talk between Hippo-TAZ and CTGF Pathways during Renal Fibrosis Progression

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis


  • Samarakoon, Rohan, Albany Medical Center, Albany, New York, United States
  • Arnouk, Alex, Albany Medical College, Watervliet, New York, United States
  • Tang, Jiaqi, Albany Medical College, Watervliet, New York, United States
  • Goldschmeding, Roel, None, Utrecht, Netherlands
  • Higgins, Paul J., Albany Medical College, Watervliet, New York, United States

TAZ is a nuclear transducer of the Hippo pathway. We recently demonstrated that TAZ, upregulated in the tubulorinterstitium in multiple models of kidney injury, is a novel profibrotic effector of the TGF-beta1 pathway that promotes CKD. Ectopic expression of TAZ in HK-2 human renal epithelial cells induces expression of CTGF, a known fibrosis causative factor. It is unknown whether CTGF upregulation deregulates Hippo-TAZ signaling during kidney fibrosis and if TAZ promotes epithelial dysfunction via CTGF-dependent mechanisms.


A novel mouse model of global conditional CTGF knockout (created by crossing CTGF-flox and ROSA26-CreET2 mice and subsequent tamoxifen administration) was utilized to determine the role of CTGF silencing on TAZ activation and renal fibrosis driven by ureteral ligation (UUO). Various transgenic HK-2 cells with stable TAZ and CTGF expression or depletion were created to investigate the potential cross-talk between TAZ and CTGF in fibrogenesis.


Fibrotic obstructed kidneys have elevated CTGF and TAZ expression relative to contralateral controls. CTGF knockout animals have attenuated renal fibrotic response and TAZ expression compared to control mice (receiving corn oil instead of tamoxifen) subjected to UUO. CTGF stable expression in HK-2 cells, furthermore, robustly induced TAZ expression and promoted fibrosis factor expression (i.e., fibronectin and collagen-1), epithelial dedifferentiation (marked by increased vimentin and decreased E-cadherin expression) and G2M cell cycle arrest. TAZ gene silencing, indeed, attenuated CTGF-mediated fibronectin, collagen-1 and vimentin expression. Similarly, fibrotic gene upregulation (e.g., CTGF and fibronectin), dedifferentiation and growth inhibition induced by stable epithelial TAZ expression were abrogated by stable CTGF suppression (via shRNA approaches).


Conditional silencing of CTGF expression during obstructive nephropathy in mice leads to attenuated TAZ expression and kidney fibrosis. Epithelial fibrotic response induced by sustained CTGF signaling requires TAZ. Conversely, TAZ induced CTGF expression orchestrates epithelial maladaptive repair, demonstrating reciprocal regulation of TAZ and CTGF in promoting CKD progression.


  • Other NIH Support