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Kidney Week

Abstract: SA-PO130

Low-Dose Verteporfin Attenuates Tubule Interstitial Fibrosis from AKI via Inhibition of YAP-MCP1-Associated Inflammation

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Zheng, Zhihuang, Department of Nephrology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • Li, Chuanlei, Department of Nephrology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • Fang, Yili, School of Basic Medical Sciences, Fudan University, Shanghai, China
  • Qi, Chenyang, School of Basic Medical Sciences, Fudan University, Shanghai, China
  • Zhang, Zhigang, School of Basic Medical Sciences, Fudan University, Shanghai, China
  • Wu, Huijuan, School of Basic Medical Sciences, Fudan University, Shanghai, China
  • Liu, Jun, Department of Nephrology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine, Shanghai, China
Background

Incomplete recovery of AKI leads to an increased risk for CKD. Tubule-interstitial fibrosis (TIF) is the main pathological features of the AKI–CKD transition. Increasing evidence indicates that YAP, downstream of Hippo pathway, might be the key regulator of renal regeneration and fibrogenesis, but its role in the renal TIF after Ischemia-reperfusion (IR)-induced AKI remained unclear.

Methods

We established bilateral renal 30min-IR-induced AKI mice model and YAP expression was examined. Then different doses of Verteporfin (VP) were injected into AKI mice intraperitoneally (every other day) for 2 weeks. Hypoxia-reoxygenation (HR) was used to mimic IR in vitro.

Results

Renal interstitial inflammation and fibrosis were gradually aggravated from 1-to-12 weeks after IR. YAP was significantly activated in the epithelium of tubules, which usually surrounded by focal inflammation and fibrosis. Two weeks injection of VP into post-IR mice with a dose of 100 mg/kg caused 100% of death (n=10), 50 mg/kg caused 85% of death (n=10) and 25mg/kg only caused 25% of death (n=10). By using Low-dose of Verteporfin (LDVP, 25mg/kg) for 2 weeks, there was no significant change in levels of SCr and BUN, but the concentration of urine electrolytes including sodium, potassium and chlorine increased. Moreover, levels of serum IL-1β,TNF-α,and MCP1 and renal positive staining for CD3 or F4/80 were reduced, compared to vehicle treated post-IR mice. Masson trichrome and Sirius red staining showed a significant reduction of collagen deposition indicating inhibited fibrogenesis. Interestingly, we found LDVP down-regulated the expression of inflammatory factor MCP1 in vitro. And hyperactivate YAP via knocking down the Lats1 could up-regulated MCP1. While IR mice treated by bindarit, a MCP1 inhibitor, levels of serum IL-1β,TNF-α,and MCP1 and renal positive staining of CD3 and F4/80 decreased as well. In addition, LDVP did not attenuate oxidative stress in vitro and tubular damage in vivo.

Conclusion

This study indicates inhibition of YAP by low-dose of Verteporfin has an anti-fibrotic effects in the progression of IR-caused AKI, which might via inhibition of YAP-MCP1 associated inflammation, whereas the higher-doses of Verteporfin has increased mortality.

Funding

  • Government Support - Non-U.S.