NLRP3 inflammasome inhibition attenuates cisplatin-induced renal fibrosis by decreasing oxidative stress and inflammation

Exp Cell Res. 2019 Oct 1;383(1):111488. doi: 10.1016/j.yexcr.2019.07.001. Epub 2019 Jul 2.

Abstract

Background/aims: The NOD-like receptor, pyrin domain containing-3 (NLRP3) inflammasome is involved in the progression of chronic kidney disease in several rodent models. Here, we investigated whether a specific inhibitor of NLRP3 inflammasome, MCC950, can attenuate cisplatin-induced renal fibrosis.

Materials: Renal fibrosis was induced via a series of three injections of cisplatin to male C57BL/6 mice (7.5 mg/kg body weight). Activation of NLRP3 inflammasome was detected by immunoblotting, real-time PCR, and immunofluorescence. To validate the protective effect of NLRP3 inflammasome inhibition, MCC950(20 mg/kg body weight) was daily injected into multiple-cisplatin-treated mice intraperitoneally for 14 days, starting from 4 weeks after the first dose of cisplatin. NLRP3-/- mice were used to confirm the role of NLRP3 inflammasome in cisplatin-induced renal fibrosis.

Results: Mice were euthanized at 6 weeks after the first dose of cisplatin treatment. In multiple-cisplatin-induced murine model, renal fibrosis was accompanied by the activation of NLRP3 inflammasome. MCC950, the specific inhibitor of NLRP3 inflammasome, reduced cisplatin-induced renal dysfunction, tubular damage, interstitial collagen deposit, and the expression of profibrotic parameters. NLRP3 inhibition might protect against cisplatin-induced renal fibrosis through the alleviation of oxidative stress and inflammation. Furthermore, inhibition of NLRP3 inflammasome activation by deleting NLRP3 gene halted the progression of cisplatin-induced renal fibrosis.

Conclusion: Inhibition of NLRP3 inflammasome attenuates renal fibrosis due to repeated cisplatin injections, and might be identified as a potential target for attenuating cisplatin-induced chronic kidney disease.

Keywords: Cisplatin; Fibrosis; NLRP3 inflammasome; Oxidative stress; Tubular epithelium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity
  • Cisplatin / toxicity*
  • Fibrosis / chemically induced
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Furans / pharmacology*
  • Humans
  • Inflammasomes / antagonists & inhibitors*
  • Inflammasomes / metabolism
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kidney Diseases / chemically induced
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Oxidative Stress / drug effects*
  • Retrospective Studies
  • Sulfonamides / pharmacology*

Substances

  • Antineoplastic Agents
  • Furans
  • Inflammasomes
  • MCC950
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Sulfonamides
  • Cisplatin