Puerarin alleviates renal ischemia/reperfusion injury by inhibiting apoptosis and endoplasmic reticulum stress via Nrf2/HO-1 pathway

Document Type : Original Article

Authors

1 Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China

2 Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China

3 Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China

Abstract

Objective(s): To explore the effects of puerarin on renal ischemia/reperfusion injury and the possible mechanism.
Materials and Methods: The experimental mice were injected with puerarin (50 or 100 mg/kg) per day or equal sterile saline by intraperitoneal injection for one week, and a renal I/R injury model was constructed. HK-2 cells were incubated with puerarin (1 uM and 10 uM) before the H/R model. Immunohistochemistry, immunocytochemistry, and Western blot analysis were used to detect the protein associated with apoptosis and endoplasmic reticulum stress.
Results: Puerarin could improve renal function and attenuate tissue structural damage after renal I/R. Meanwhile, puerarin alleviated apoptosis and endoplasmic reticulum stress by decreasing expression levels of specific biomarkers such as caspase-3, GRP78, CHOP, and p-elF2α/ elF2α in animals and HK-2 cells. The up-regulated expression of Nrf2 and HO-1 protein after puerarin treatment indicated that the Nrf2/HO-1 signaling pathway might mediate the protective mechanism of puerarin against renal I/R.
Conclusion: Our results suggest that puerarin alleviated renal ischemia/reperfusion injury by inhibiting apoptosis and endoplasmic reticulum stress via the Nrf2/HO-1 pathway and offered new insights for preventing and treating renal I/R.

Keywords

Main Subjects

References

1. Chen J, Xu C, Yang K, Gao R, Cao Y, Liang L, et al. Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment. Nat Commun 2023; 14: 1161-1177.
2. Shao G, He J, Meng J, Ma A, Geng X, Zhang S, et al. Ganoderic acids prevent renal ischemia reperfusion injury by inhibiting inflammation and apoptosis. Int J Mol Sci 2021; 22: 1029-1043.
3. Tang C, Han H, Liu Z, Liu Y, Yin L, Cai J, et al. Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury. Cell Death Dis 2019; 10: 677-691.
4. Tajima T, Yoshifuji A, Matsui A, Itoh T, Uchiyama K, Kanda T, et al. Beta-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects. Kidney Int 2019; 95: 1120-1137.
5. Pan B, Sun J, Liu Z, Wang L, Huo H, Zhao Y, et al. Longxuetongluo capsule protects against cerebral ischemia/reperfusion injury through endoplasmic reticulum stress and MAPK-mediated mechanisms. J Adv Res 2021; 33: 215-225.
6. Zhu YL, Huang J, Chen XY, Xie J, Yang Q, Wang JF, et al. Senkyunolide I alleviates renal Ischemia-Reperfusion injury by inhibiting oxidative stress, endoplasmic reticulum stress and apoptosis. Int Immunopharmacol 2022; 102: 108393.
7. Tang C, Hu Y, Gao J, Jiang J, Shi S, Wang J, et al. Dexmedetomidine pretreatment attenuates myocardial ischemia reperfusion induced acute kidney injury and endoplasmic reticulum stress in human and rat. Life Sci 2020; 257: 118004.
8. Zhang Y, Yang X, Ge X, Zhang F. Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice. Biomed Pharmacother 2019; 109: 726-733.
9. Gao M, Zhang Z, Lai K, Deng Y, Zhao C, Lu Z, et al. Puerarin: A protective drug against ischemia-reperfusion injury. Front Pharmacol 2022; 13: 927611-927620.
10. Wang ZK, Chen RR, Li JH, Chen JY, Li W, Niu XL, et al. Puerarin protects against myocardial ischemia/reperfusion injury by inhibiting inflammation and the NLRP3 inflammasome: The role of the SIRT1/NF-kappaB pathway. Int Immunopharmacol 2020; 89: 107086.
11. Zheng M, Song D, Luo Z, Lu Z, Wu Y ,Wang W. Effect of puerarin on expression of Fas/FasL mRNA in pulmonary injury induced by ischemia-reperfusion in rabbits. Nat Prod Commun 2015; 10: 253-256.
12. Zhang Q, Yao M, Qi J, Song R, Wang L, Li J, et al. Puerarin inhibited oxidative stress and alleviated cerebral ischemia-reperfusion injury through PI3K/Akt/Nrf2 signaling pathway. Front Pharmacol 2023; 14: 1134380-113493.
13. Ma Y, Gai Y, Yan J, Li J, Zhang Y. Puerarin attenuates anoxia/reoxygenation injury through enhancing Bcl-2 associated athanogene 3 expression, a modulator of apoptosis and autophagy. Med Sci Monit 2016; 22: 977-983.
14. Guan L, Li C, Zhang Y, Gong J, Wang G, Tian P, et al. Puerarin ameliorates retinal ganglion cell damage induced by retinal ischemia/reperfusion through inhibiting the activation of TLR4/NLRP3 inflammasome. Life Sci 2020; 256: 117935.
15. Wang JF, Mei ZG, Fu Y, Yang SB, Zhang SZ, Huang WF, et al. Puerarin protects rat brain against ischemia/reperfusion injury by suppressing autophagy via the AMPK-mTOR-ULK1 signaling pathway. Neural Regen Res 2018; 13: 989-998.
16. Wu Z, Li C, Li Q, Li J, Lu X. Puerarin alleviates cisplatin-induced acute renal damage and upregulates microRNA-31-related signaling. Exp Ther Med 2020; 20: 3122-3129.
17. Fang X, Lan X, Zhu M, He M, Sun M, Cao Y, et al. Puerarin induces macrophage M2 polarization to exert antinonalcoholic steatohepatitis pharmacological activity via the activation of autophagy. J Agric Food Chem 2024; 72: 7187-7202.
18. Huang Q, Wang L, Ran Q, Wang J, Wang C, He H, et al. Notopterol-induced apoptosis and differentiation in human acute myeloid leukemia HL-60 cells. Drug Des Devel Ther 2019; 13: 1927-1940.
19. Zhang J, Bi J, Ren Y, Du Z, Li T, Wang T, et al. Involvement of GPX4 in irisin’s protection against ischemia reperfusion-induced acute kidney injury. J Cell Physiol 2021; 236: 931-945.
20. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017; 171: 273-285.
21. Wu R, Li J, Tu G, Su Y, Zhang X, Luo Z, et al. Comprehensive molecular and cellular characterization of acute kidney injury progression to renal fibrosis. Front Immunol 2021; 12: 699192-699199. 
22. Zwaini Z, Dai H, Stover C, Yang B. Role of complement properdin in renal ischemia-reperfusion injury. Curr Gene Ther 2017; 17: 411-423.
23. Hou N, Huang Y, Cai SA, Yuan WC, Li LR, Liu XW, et al. Puerarin ameliorated pressure overload-induced cardiac hypertrophy in ovariectomized rats through activation of the PPARalpha/PGC-1 pathway. Acta Pharmacol Sin 2021; 42: 55-67.
24. Han Y, Wang H, Wang Y, Dong P, Jia J ,Yang S. Puerarin protects cardiomyocytes from ischemia-reperfusion injury by upregulating LncRNA ANRIL and inhibiting autophagy. Cell Tissue Res 2021; 385: 739-751.
25. Sang HF, Mei QB, Xu LX, Wang Q, Cheng H ,Xiong LZ. Effect of puerarin on neural function and histopathological damages after transient spinal cord ischemia in rabbits. Chin J Traumatol 2004; 7: 143-147.
26. Zhu Q, Yang S, Wei C, Lu G, Lee K, He JC, et al. Puerarin attenuates diabetic kidney injury through interaction with Guanidine nucleotide-binding protein Gi subunit alpha-1 (Gnai1) subunit. J Cell Mol Med 2022; 26: 3816-3827.
27. Li X, Cai W, Lee K, Liu B, Deng Y, Chen Y, et al. Puerarin attenuates diabetic kidney injury by suppressing NOX4 expression in podocytes. Sci Rep 2017; 7: 14603-14623. 
28. Li X, Zhu Q, Zheng R, Yan J, Wei M, Fan Y, et al. Puerarin attenuates diabetic nephropathy by promoting autophagy in podocytes. Front Physiol 2020; 11: 73-83.
29. Ma JQ, Ding J, Xiao ZH, Liu CM. Puerarin ameliorates carbon tetrachloride-induced oxidative DNA damage and inflammation in mouse kidney through ERK/Nrf2/ARE pathway. Food Chem Toxicol 2014; 71: 264-271.
30. Ma X, Yan L, Zhu Q, Shao F. Puerarin attenuates cisplatin-induced rat nephrotoxicity: The involvement of TLR4/NF-kappaB signaling pathway. PLoS One 2017; 12: e0171612-171624.
31. Liu G, Zhang K, Dong W, Tan Y, Long M, Zou H, et al. Puerarin restores the autophagic flux to alleviate cadmium‑induced endoplasmic reticulum stress in NRK‑52E cells. Mol Med Rep 2020; 22: 2551-2563.
32. Song XB, Liu G, Wang ZY, Wang L. Puerarin protects against cadmium-induced proximal tubular cell apoptosis by restoring mitochondrial function. Chem Biol Interact 2016; 260: 219-231.
33. Liu Q, Liu Z, Huo X, Wang C, Meng Q, Sun H, et al. Puerarin improves methotrexate-induced renal damage by up-regulating renal expression of Oat1 and Oat3 in vivo and in vitro. Biomed Pharmacother 2018; 103: 915-922. 
34. Wang J, Ge S, Wang Y, Liu Y, Qiu L, Li J, et al. Puerarin alleviates UUO-induced inflammation and fibrosis by regulating the NF-kappaB P65/STAT3 and TGFbeta1/Smads signaling pathways. Drug Des Devel Ther 2021; 15: 3697-3708.
35. Yang J, Li B, Wang J, Fan W. Inhibition of pyroptosis of renal tubular epithelial cells by puerarin via regulation of lncRNA NEAT1 ameliorating chronic renal failure. Iran J Kidney Dis 2024; 1: 18-26.
36. Liu K, Lan D, Li C, Liu S, Dai X, Song T, et al. A double-edged sword: Role of apoptosis repressor with caspase recruitment domain (ARC) in tumorigenesis and ischaemia/reperfusion (I/R) injury. Apoptosis 2023; 28: 313-325.
37. Xu Y, Guo M, Jiang W, Dong H, Han Y, An XF, et al. Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury. Ren Fail 2016; 38: 831-837.
38. Shen X, Zhang K, Kaufman RJ. The unfolded protein response--a stress signaling pathway of the endoplasmic reticulum. J Chem Neuroanat 2004; 28: 79-92.
39. Porter AW, Brodsky JL ,Buck TM. Emerging links between endoplasmic reticulum stress responses and acute kidney injury. Am J Physiol Cell Physiol 2022; 323: C1697-C703.
40. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 2004; 18: 3066-3077.
41. Zhang J, Zhang J, Ni H, Wang Y, Katwal G, Zhao Y, et al. Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation. Cell Death Discov 2021; 7: 44-56.
42. Wang J, Lu L, Chen S, Xie J, Lu S, Zhou Y, et al. Up-regulation of PERK/Nrf2/HO-1 axis protects myocardial tissues of mice from damage triggered by ischemia-reperfusion through ameliorating endoplasmic reticulum stress. Cardiovasc Diagn Ther 2020; 10: 500-511.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 2
February 2025
Pages 187-193

Files

Share

How to cite

Statistics