[논문]Capsaicin Ameliorates Cisplatin-Induced Renal Injury through Induction of Heme Oxygenase-1

Jung, Sung-Hyun; Kim, Hyung-Jin; Oh, Gi-Su; Shen, AiHua; Lee, Subin; Choe, Seong-Kyu; Park, Raekil; So, Hong-Seob

doi:10.14348/molcells.2014.2322

Capsaicin Ameliorates Cisplatin-Induced Renal Injury through Induction of Heme Oxygenase-1 원문보기

Molecules and cells, v.37 no.3, 2014년, pp.234 - 240

Jung, Sung-Hyun (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine) , Kim, Hyung-Jin (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine) , Oh, Gi-Su (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine) , Shen, AiHua (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine) , Lee, Subin (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine) , Choe, Seong-Kyu (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine) , Park, Raekil (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine) , So, Hong-Seob (Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine)

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Cisplatin is one of the most potent chemotherapy agents. However, its use is limited due to its toxicity in normal tissues, including the kidney and ear. In particular, nephrotoxicity induced by cisplatin is closely associated with oxidative stress and inflammation. Heme oxygenase-1(HO-1), the rate-limiting enzyme in the heme metabolism, has been implicated in a various cellular processes, such as inflammatory injury and anti-oxidant/oxidant homeostasis. Capsaicin is reported to have therapeutic potential in cisplatin-induced renal failures. However, the mechanisms underlying its protective effects on cisplatin-induced nephrotoxicity remain largely unknown. Herein, we demonstrated that administration of capsaicin ameliorates cisplatin-induced renal dysfunction by assessing the levels of serum creatinine and blood urea nitrogen (BUN) as well as tissue histology. In addition, capsaicin treatment attenuates the expression of inflammatory mediators and oxidative stress markers for renal damage. We also found that capsaicin induces HO-1 expression in kidney tissues and HK-2 cells. Notably, the protective effects of capsaicin were completely abrogated by treatment with either the HO inhibitor ZnPP IX or HO-1 knockdown in HK-2 cells. These results suggest that capsaicin has protective effects against cisplatin-induced renal dysfunction through induction of HO-1 as well as inhibition oxidative stress and inflammation.

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Total kidney lysate was blotted and probed with an anti-TLR4 antibody (upper panel). (D) The blots were reprobed with an anti-actin antibody. Densitometric analyses are presented as the relative ratio of TLR4 to actin (lower panel).

제안 방법

However, the mechanisms underlying the antioxidant and protective effects of capsaicin were poorly understood. In this study, we attempted to investigate the possible molecular mechanisms underlying the cytoprotective effects of capsaicin with prime focus on the upregulation of HO-1. HO-1 is an enzyme with potent antioxidant activity, and upregulation of HO-1 expression is recognized as a key event to maintain cellular antioxidant capacity.
Primers used were as follows: mouse HO-1, 5′-GGT GAT GGC TTC CTT GTA CC-3′ and 5′-AGT GAG GCC CAT ACC AGA AG-3′; human HO-1, 5′-CAT GAC ACC AAG GAC CAG AG-3′ and 5′-AGT GTA AGG ACC CAT CGG AG-3′; mouse NQO1, 5′-AGC CCA GAT ATT GTG GCC G-3′ and 5′-CGT TTC AGA ATG GTC GGC AC-3′; mouse GCLC, 5′-CTG CAC ATC TAC CAC GCA GT-3′ and 5′-GTC TCA AGA ACA TCG CCT CC-3′; mouse GCLM, 5′-CGG GAA CCT GCT CAA CTG-3′ and 5′-CCA AAA CAT CTG GAA ACT CCC-3′; mouse GSS, 5′-GAA GCA GCT CGA AGA ACT GG-3′ and 5′-AGC ACT GGG TAC TGG TGA GG-3′; GAPDH, 5′-TCC CAC TCT TCC ACC TTC GA-3′ and 5′-AGT TGG GAT AGG GCC TCT CTT G-3′.
Three micrograms of RNA was converted to cDNA using the First Strand cDNA Synthesis Superscript kit (Invitrogen) according to the manufacturer’s protocol. Quantitative real-time PCR was performed with 10 pmol of primers for HO-1 and GAPDH using SYBR Green Mastermix (Invitrogen). Reactions were performed in triplicate and specificity was monitored using melting curve analysis after cycling.
To evaluate the effects of capsaicin on renal function, C57BL/6 mice were treated with capsaicin, cisplatin, or capsaicin plus cisplatin according to the experimental schedule described in the “Materials and Methods”, and the levels of serum creatinine and BUN were measured.

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of triplicate analyses. Statistical multivariate analysis was performed by analysis of variance and Duncan tests, using the SPSS 11 (USA) statistical software. Two-way ANOVA and/or one-way ANOVA were used to determine the significance of the results.
Statistical multivariate analysis was performed by analysis of variance and Duncan tests, using the SPSS 11 (USA) statistical software. Two-way ANOVA and/or one-way ANOVA were used to determine the significance of the results. The statistical results were reviewed by a masters-level biostatistician.

이론/모형

05 by one-way ANOVA compared with the control (n = 3). (E-G) Cell viability was determined by MTT assay. Cell viability was expressed as a percentage of controls.

성능/효과

Therefore, it remains unclear which gene(s) cooperate with HO-1 that could confer the protective effects of capsaicin against cisplatin-induced nephrotoxicity. In conclusion, we showed that capsaicin ameliorates cisplatin-induced nephrotoxicity by effectively suppressing oxidative damages and inflammatory responses, and that HO-1 induction is central to the protective mechanism of capsaicin. In the present study, we suggest that the activation of HO-1 by the regular intake of natural phytochemicals may represent one of the most practical and feasible ways to reduce the risk of cisplatin-induced toxicity.

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Capsaicin Ameliorates Cisplatin-Induced Renal Injury through Induction of Heme Oxygenase-1 원문보기

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Capsaicin Ameliorates Cisplatin-Induced Renal Injury through Induction of Heme Oxygenase-1 원문보기

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