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Abstract: SA-OR069

NLRP3 Inflammasome Inhibition Attenuates Cisplatin-Induced Renal Fibrosis by Decreasing Oxidative Stress and Inflammation

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Shu, Li, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • Lin, Qisheng, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • Shao, Xinghua, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • Ni, Zhaohui, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Group or Team Name

  • Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
Background

The mechanisms of cisplatin-induced chronic kidney disease are ill-defined.

Methods

Renal fibrosis was induced via a series of three injections of cisplatin to male C57BL/6 mice (7.5mg/kg body weight), and mice were euthanized at 6 weeks after the first cisplatin treatment. To validate the protective effect of NLRP3 inflammasome inhibition, MCC950 or gene deletion was used.

Results

Male C57BL/6 mice were administered three doses of cisplatin. BUN and serum creatinine increased time-dependently, accompanied tubular interstitial fibrosis. The protein level of NLRP3, ASC, and caspase-1 maturation was upregulated, and expression of IL-1β was markedly increased in renal tubular epithelium . MCC950, the specific inhibitor of NLRP3 inflammasome, was daily injected into multiple-cisplatin-treated mice intraperitoneally(20mg/kg body weight) for 14 days, starting from 4 weeks after the third dose of cisplatin. MCC950 reduced renal dysfunction, tubular damage, interstitial collagen deposit, and the expression of profibrotic parameters. MCC950 treatment also alleviated oxidative stress and inflammation. Furthermore, NLRP3 gene knockout halted the progression of cisplatin-induced renal fibrosis.

Conclusion

The activation of NLRP3 inflammasome promoted renal dysfunction and interstitial fibrosis induced by multiple injections of low-dose cisplatin. Blockade of NLRP3 inflammasome, by a selective inhibitor of NLRP3 inflammasome, MCC950, or by genetic NLRP3 deficiency, attenuated cisplatin-induced oxidative stress, inflammation, renal injury and fibrosis.

Fig.1 Multiple-cisplatin injections induces renal fibrosis.
Fig.2 NLRP3 inflammasome is activated in RTPC.
Fig.3 MCC950 inhibits NLRP3 inflammasome activation .
Fig.4 MCC950 alleviates cisplatin-induced chronic renal injury.

Fig.5 MCC950 attenuates CP-induced renal interstitial fibrosis.
Fig.6 MCC950 attenuates CP-induced oxidative stress and inflammation.
Fig.7 NLRP3 deletion inhibits inflammasome activation and inflammation .
Fig.8 NLRP3 knockout attenuates CP-induced renal injury and fibrosis.

Funding

  • Government Support - Non-U.S.