Inhibition of Yes-Associated Protein by Verteporfin Ameliorates Unilateral Ureteral Obstruction-Induced Renal Tubulointerstitial Inflammation and Fibrosis.

Jixiu Jin,Tian Wang,Won Kim,Wenjia Li,Woong Park,Sung Kwang Park,Kyung Pyo Kang

doi:10.3390/ijms21218184

Abstract

Yes-associated protein (YAP) activation after acute ischemic kidney injury might be related to interstitial fibrosis and impaired renal tubular regeneration. Verteporfin (VP) is a photosensitizer used in photodynamic therapy to treat age-related macular degeneration. In cancer cells, VP inhibits TEA domain family member (TEAD)-YAP interactions without light stimulation. The protective role of VP in unilateral ureteral obstruction (UUO)-induced renal fibrosis and related mechanisms remains unclear. In this study, we investigate the protective effects of VP on UUO-induced renal tubulointerstitial inflammation and fibrosis and its regulation of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We find that VP decreased the UUO-induced increase in tubular injury, inflammation, and extracellular matrix deposition in mice. VP also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells by modulating Smad2 and Smad3 phosphorylation. Therefore, YAP inhibition might have beneficial effects on UUO-induced tubulointerstitial inflammation and fibrosis by regulating the TGF-β1/Smad signaling pathway.

Highlights

Chronic kidney disease (CKD) is a heterogeneous condition characterized by reduced glomerular filtration rate, glomerular sclerosis, tubular atrophy, and interstitial fibrosis with inflammatory cell infiltration [1]
VP treatment decreased the ureteral obstruction (UUO)-induced increase in tubular dilation, inflammatory cell infiltration, and tubulointerstitial fibrosis compared with Veh-treated UUO kidneys (Figure 1A)
We found that inhibiting the TGF/Smad signaling pathway by modulating estrogen receptor α and activating mitochondrial Sirt3 ameliorated UUO-induced renal inflammation and fibrosis [9,21]

Summary

Introduction

Chronic kidney disease (CKD) is a heterogeneous condition characterized by reduced glomerular filtration rate, glomerular sclerosis, tubular atrophy, and interstitial fibrosis with inflammatory cell infiltration [1]. As human life expectancy has increased, CKD has become one of the most common non-communicable diseases [2,3]. End-stage renal disease that requires renal replacement therapy such as dialysis or kidney transplantation is associated with a decrease in residual life expectancy compared with healthy individuals [3]. Despite plenty of health resources in developed countries, CKD’s global burden is steadily increasing, and CKD-related mortality is increasing [4]. Strategies to enable the early recognition and prevention of CKD are needed to decrease the global health burden

Methods

Results

Conclusion