CB 1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model

Partha Mukhopadhyay, Hao Pan, Mohanraj Rajesh, Sándor Bátkai, Vivek Patel, Judith Harvey-White, Bani Mukhopadhyay, György Haskó, Bin Gao, Ken MacKie, Pál Pacher

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)

Abstract

Background and purpose: Accumulating recent evidence suggests that cannabinoid-1 (CB 1) receptor activation may promote inflammation and cell death and its pharmacological inhibition is associated with anti-inflammatory and tissue-protective effects in various preclinical disease models, as well as in humans. Experimental approach: In this study, using molecular biology and biochemistry methods, we have investigated the effects of genetic deletion or pharmacological inhibition of CB 1 receptors on inflammation, oxidative/nitrosative stress and cell death pathways associated with a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. Results: Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen-activated protein kinases (MAPKs), apoptotic and poly (ADP-ribose)polymerase-dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor-α and interleukin-1β) and promoted oxidative/nitrosative stress [increased expressions of superoxide-generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4-hydroxynonenal and nitrotyrosine levels] in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB 1 receptors with AM281 or SR141716 markedly attenuated the cisplatin-induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney. Conclusions and implications: The endocannabinoid system through CB 1 receptors promotes cisplatin-induced tissue injury by amplifying MAPK activation, cell death and interrelated inflammation and oxidative/nitrosative stress. These results also suggest that inhibition of CB 1 receptors may exert beneficial effects in renal (and most likely other) diseases associated with enhanced inflammation, oxidative/nitrosative stress and cell death.

Original languageEnglish
Pages (from-to)657-668
Number of pages12
JournalBritish Journal of Pharmacology
Volume160
Issue number3
DOIs
Publication statusPublished - Jun 2010
Externally publishedYes

Keywords

  • Cannabinoid receptors
  • Endocannabinoids
  • Nephropathy

ASJC Scopus subject areas

  • Pharmacology

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