Formononetin protects against cisplatin‑induced acute kidney injury through activation of the PPARα/Nrf2/HO‑1/NQO1 pathway

Hao,Yan; Miao,Jie; Liu,Wenjia; Peng,Li; Chen,Yue; Zhong,Qing

doi:10.3892/ijmm.2020.4805

Formononetin protects against cisplatin‑induced acute kidney injury through activation of the PPARα/Nrf2/HO‑1/NQO1 pathway

Authors:
- Yan Hao
- Jie Miao
- Wenjia Liu
- Li Peng
- Yue Chen
- Qing Zhong
View Affiliations

Affiliations: Department of Nephrology, Zigong First People's Hospital, Zigong, Sichuan 643000, P.R. China, Department of Imaging Medicine, Sichuan Vocational College of Health and Rehabilitation, Zigong, Sichuan 643000, P.R. China
Published online on: December 1, 2020 https://doi.org/10.3892/ijmm.2020.4805
Pages: 511-522
Copyright: © Hao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute kidney injury (AKI) is characterized by an abrupt deterioration of renal function. Formononetin (FOR) protects against cisplatin (CIS)‑induced AKI, and it has various potential pharmacological and biological effects, including anti‑inflammatory, antioxidative and anti‑apoptotic effects. The current study investigated the role of FOR in CIS‑induced AKI. Rats were treated with CIS to establish an AKI model, followed by treatment with FOR. HK‑2 cells were treated with CIS, FOR, GW6471 [a peroxisome proliferator‑activated receptor α (PPARα) antagonist], eupatilin (a PPARα agonist) and nuclear factor erythroid 2‑related factor 2 (Nrf2) small interfering RNA (siNrf2), and cell proliferation and apoptosis were determined by MTT and flow cytometry assays. The mRNA and proteins levels of PPARα, Nrf2, heme oxygenase‑1 (HO‑1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were measured by reverse transcription‑quantitative PCR and western blotting. The results demonstrated that FOR attenuated the histopathological changes, the levels of blood urea nitrogen, creatinine, TNF‑α and IL‑1β, and the MDA content and MPO activity, whereas it enhanced CAT activity in the AKI rat model. Furthermore, FOR and eupatilin promoted cell viability and CAT activity, and increased the levels of PPARα, Nrf2 and HO‑1 and NQO1, but suppressed apoptosis and MPO activity, and reduced the levels of MDA, TNF‑α and IL‑1β in CIS‑treated HK‑2 cells. Notably, the aforementioned effects were reversed by GW6471 treatment or siNrf2 transfection. In conclusion, FOR protects against CIS‑induced AKI via activation of the PPARα/Nrf2/HO‑1/NQO1 pathway.

View Figures

View References

1	Lee YJ, Chan JP, Hsu WL, Lin KW and Chang CC: Prognostic factors and a prognostic index for cats with acute kidney injury. J Vet Intern Med. 26:500–505. 2012. View Article : Google Scholar : PubMed/NCBI
2	Farrar A: Acute kidney injury. Nurs Clin North Am. 53:499–510. 2018. View Article : Google Scholar : PubMed/NCBI
3	Brix S and Stahl R: Acute kidney injury. Dtsch Med Wochenschr. 142:290–300. 2017.In German. PubMed/NCBI
4	Ni J, Hou X, Wang X, Shi Y, Xu L, Zheng X, Liu N, Qiu A and Zhuang S: 3-deazaneplanocin A protects against cisplatin-induced renal tubular cell apoptosis and acute kidney injury by restoration of E-cadherin expression. Cell Death Dis. 10:3552019. View Article : Google Scholar : PubMed/NCBI
5	de Almeida CDC, Simões E, Silva AC, de Queiroz Oliveira JA, Batista ISF, Pereira FH, Gonçalves JE, Nobre V and Martins MAP: Vancomycin-associated nephrotoxicity in non-critically ill patients admitted in a Brazilian public hospital: A prospective cohort study. PLoS One. 14:e02220952019. View Article : Google Scholar : PubMed/NCBI
6	Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, Liu KD, Mehta RL, Pannu N, Van Biesen W and Vanholder R: Acute kidney injury: An increasing global concern. Lancet. 382:170–179. 2013. View Article : Google Scholar : PubMed/NCBI
7	Rashid S, Nafees S, Siddiqi A, Vafa A, Afzal SM, Parveen R, Ali N, Hasan SK, Barnwal P, Shahid A and Sultana S: Partial protection by 18β glycrrhetinic acid against cisplatin induced oxidative intestinal damage in wistar rats: Possible role of NFkB and caspases. Pharmacol Rep. 69:1007–1013. 2017. View Article : Google Scholar : PubMed/NCBI
8	Lee H, Lee D, Kang KS, Song JH and Choi YK: Inhibition of intracellular ROS accumulation by formononetin attenuates cisplatin-mediated apoptosis in LLC-PK1 cells. Int J Mol Sci. 19:8132018. View Article : Google Scholar :
9	Li J, Jiang K, Qiu X, Li M, Hao Q, Wei L, Zhang W, Chen B and Xin X: Overexpression of CXCR4 is significantly associated with cisplatin-based chemotherapy resistance and can be a prognostic factor in epithelial ovarian cancer. BMB Rep. 47:33–38. 2014. View Article : Google Scholar :
10	Park JY, Lee D, Jang HJ, Jang DS, Kwon HC, Kim KH, Kim SN, Hwang GS, Kang KS and Eom DW: Protective effect of artemisia asiatica extract and its active compound eupatilin against cisplatin-induced renal damage. Evid Based Complement Alternat Med. 2015:4839802015. View Article : Google Scholar : PubMed/NCBI
11	Zhang YZ, Zhang J, Tan L, Xia Z, Wang CZ, Zhou LD, Zhang Q and Yuan CS: Preparation and evaluation of temperature and magnetic dual-responsive molecularly imprinted polymers for the specific enrichment of formononetin. J Sep Sci. 41:3060–3068. 2018. View Article : Google Scholar : PubMed/NCBI
12	Huang D, Wang C, Duan Y, Meng Q, Liu Z, Huo X, Sun H, Ma X and Liu K: Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury. Toxicol Appl Pharmacol. 326:15–24. 2017. View Article : Google Scholar : PubMed/NCBI
13	Chtourou Y, Aouey B, Aroui S, Kebieche M and Fetoui H: Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat. Chem Biol Interact. 243:1–9. 2016. View Article : Google Scholar
14	Ning C, Gao X, Wang C, Huo X, Liu Z, Sun H, Yang X, Sun P, Ma X, Meng Q and Liu K: Protective effects of ginsenoside Rg1 against lipopolysaccharide/d-galactosamine-induced acute liver injury in mice through inhibiting toll-like receptor 4 signaling pathway. Int Immunopharmacol. 61:266–276. 2018. View Article : Google Scholar : PubMed/NCBI
15	Hwang JS, Kang ES, Han SG, Lim DS, Paek KS, Lee CH and Seo HG: Formononetin inhibits lipopolysaccharide-induced release of high mobility group box 1 by upregulating SIRT1 in a PPARδ-dependent manner. Peer J. 6:e42082018. View Article : Google Scholar
16	Mu H, Bai YH, Wang ST, Zhu ZM and Zhang YW: Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine. 16:314–319. 2009. View Article : Google Scholar
17	Nguyen LTH, Nguyen UT, Kim YH, Shin HM and Yang IJ: Astragali Radix and its compound formononetin ameliorate diesel particulate matter-induced skin barrier disruption by regulation of keratinocyte proliferation and apoptosis. J Ethnopharmacol. 228:132–141. 2019. View Article : Google Scholar
18	Huang D, Wang C, Meng Q, Liu Z, Huo X, Sun H, Yang S, Ma X, Peng J and Liu K: Protective effects of formononetin against rhabdomyolysis-induced acute kidney injury by upregulating NRF2 in vivo and in vitro. RSC Adv. 6:110874–110883. 2016. View Article : Google Scholar
19	Gonzalez-Manan D, D'Espessailles A, Dossi CG, San Martin M, Mancilla RA and Tapia GS: Rosa mosqueta oil prevents oxidative stress and inflammation through the upregulation of PPAR-α and NRF2 in C57BL/6J mice fed a high-fat diet. J Nutr. 147:579–588. 2017. View Article : Google Scholar
20	Wang WR, Liu EQ, Zhang JY, Li YX, Yang XF, He YH, Zhang W, Jing T and Lin R: Activation of PPAR alpha by fenofibrate inhibits apoptosis in vascular adventitial fibroblasts partly through SIRT1-mediated deacetylation of FoxO1. Exp Cell Res. 338:54–63. 2015. View Article : Google Scholar : PubMed/NCBI
21	Yang S, Wei L, Xia R, Liu L, Chen Y, Zhang W, Li Q, Feng K, Yu M, Zhang W, et al: Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα. Biochem Biophys Res Commun. 512:770–778. 2019. View Article : Google Scholar : PubMed/NCBI
22	Shen J, Rasmussen M, Dong QR, Tepel M and Scholze A: Expression of the NRF2 target gene NQO1 is enhanced in mono-nuclear cells in human chronic kidney disease. Oxid Med Cell Longev. 2017:90918792017. View Article : Google Scholar
23	Cao SS, Yan M, Hou ZY, Chen Y, Jiang YS, Fan XR, Fang PF and Zhang BK: Danshen modulates Nrf2-mediated signaling pathway in cisplatin-induced renal injury. J Huazhong Univ Sci Technolog Med Sci. 37:761–765. 2017.PubMed/NCBI
24	Shelton LM, Park BK and Copple IM: Role of Nrf2 in protection against acute kidney injury. Kidney Int. 84:1090–1095. 2013. View Article : Google Scholar : PubMed/NCBI
25	Ansari MA: Sinapic acid modulates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Biomed Pharmacother. 93:646–653. 2017. View Article : Google Scholar : PubMed/NCBI
26	Shen Y, Qiu T, Liu XH, Zhang L, Wang ZS and Zhou JQ: Renal ischemia-reperfusion injury attenuated by splenic ischemic preconditioning. Eur Rev Med Pharmacol Sci. 22:2134–2142. 2018.PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Method. 25:402–408. 2001. View Article : Google Scholar
28	Camano S, Lazaro A, Moreno-Gordaliza E, Torres AM, de Lucas C, Humanes B, Lazaro JA, Milagros Gomez-Gomez M, Bosca L and Tejedor A: Cilastatin attenuates cisplatin-induced proximal tubular cell damage. J Pharmacol Exp Ther. 334:419–429. 2010. View Article : Google Scholar : PubMed/NCBI
29	Pabla N and Dong Z: Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney Int. 73:994–1007. 2008. View Article : Google Scholar : PubMed/NCBI
30	Coelho S, Cabral G, Lopes JA and Jacinto A: Renal regeneration after acute kidney injury. Nephrology (Carlton). 23:805–814. 2018. View Article : Google Scholar
31	Iwaki T, Bennion BG, Stenson EK, Lynn JC, Otinga C, Djukovic D, Raftery D, Fei L, Wong HR, Liles WC and Standage SW: PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis. Physiol Rep. 7:e140782019. View Article : Google Scholar
32	Kong W, Fu J, Liu N, Jiao C, Guo G, Luan J, Wang H, Yao L, Wang L, Yamamoto M, et al: Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction. Nephrol Dial Transplant. 33:771–783. 2018. View Article : Google Scholar
33	Zoja C, Benigni A and Remuzzi G: The Nrf2 pathway in the progression of renal disease. Nephrol Dial Transplant. 29(Suppl 1): i19–i24. 2014. View Article : Google Scholar
34	Ruiz S, Pergola PE, Zager RA and Vaziri ND: Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 83:1029–1041. 2013. View Article : Google Scholar : PubMed/NCBI
35	Aladaileh SH, Hussein OE, Abukhalil MH, Saghir SAM, Bin-Jumah M, Alfwuaires MA, Germoush MO, Almaiman AA and Mahmoud AM: Formononetin upregulates Nrf2/HO-1 signaling and prevents oxidative stress, inflammation, and kidney injury in methotrexate-induced rats. Antioxidants (Basel). 8:4302019. View Article : Google Scholar
36	AL Haithloul HAS, Alotaibi MF, Bin-Jumah M, Elgebaly H and Mahmoud AM: Olea europaea leaf extract up-regulates Nrf2/ARE/HO-1 signaling and attenuates cyclophos-phamide-induced oxidative stress, inflammation and apoptosis in rat kidney. Biomed Pharmacother. 111:676–685. 2019. View Article : Google Scholar
37	Gang GT, Kim YH, Noh JR, Kim KS, Jung JY, Shong M, Hwang JH and Lee CH: Protective role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in cisplatin-induced nephrotoxicity. Toxicol Lett. 221:165–175. 2013. View Article : Google Scholar : PubMed/NCBI