Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Research Article

Crocin Ameliorates Diabetic Nephropathy through Regulating Metabolism, CYP4A11/PPARγ, and TGF-β/Smad Pathways in Mice

Author(s): Wei Chen, Jinhao Su, Yubin Liu, Tianmei Gao, Xiaohui Ji, Hanzhou Li, Huajun Li, Yuansong Wang, Hui Zhang and Shuquan Lv*

Volume 24, Issue 10, 2023

Published on: 02 November, 2023

Page: [709 - 722] Pages: 14

DOI: 10.2174/0113892002257928231031113337

Price: $65

conference banner
Abstract

Introduction: Crocin is one of the main components of Crocus sativus L. and can alleviate oxidative stress and inflammation in diabetic nephropathy (DN). However, the specific mechanism by which crocin treats DN still needs to be further elucidated.

Method: In the present study, a mouse model of DN was first established to investigate the therapeutic effect of crocin on DN mice. Subsequently, non-targeted metabolomics techniques were used to analyze the mechanisms of action of crocin in the treatment of DN. The effects of crocin on CYP4A11/PPARγ and TGF-β/Smad pathway were also investigated.

Result: Results showed that crocin exhibited significant therapeutic and anti-inflammatory, and anti-oxidative effects on DN mice. In addition, the non-targeted metabolomics results indicated that crocin treatment affected several metabolites in kidney. These metabolites were mainly associated with biotin metabolism, riboflavin metabolism, and arachidonic acid metabolism. Furthermore, crocin treatment upregulated the decreased levels of CYP4A11 and phosphorylated PPARγ, and reduced the increased levels of TGF-β1 and phosphorylated Smad2/3 in the kidneys of DN mice.

Conclusion: In conclusion, our study validated the considerable therapeutic, anti-inflammatory, and antioxidative impacts of crocin on DN mice. The mechanism of crocin treatment may be related to the regulation of biotin riboflavin and arachidonic acid metabolism, the activation of CYP4A11/PPARγ pathway, and the inhibition of TGF-β/Smad pathway in the kidney.

Graphical Abstract

[1]
Xiang, E.; Han, B.; Zhang, Q.; Rao, W.; Wang, Z.; Chang, C.; Zhang, Y.; Tu, C.; Li, C.; Wu, D. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis; Stem Cell Res. Amp. Ther, 2020, p. 11.
[2]
Yuan, S.; Wang, Y.; Li, Z.; Chen, X.; Song, P.; Chen, A.; Qu, Z.; Wen, S.; Liu, H.; Zhu, X.; Gasdermin, D. Gasdermin D is involved in switching from apoptosis to pyroptosis in TLR4-mediated renal tubular epithelial cells injury in diabetic kidney disease. Arch. Biochem. Biophys., 2022, 727, 109347.
[http://dx.doi.org/10.1016/j.abb.2022.109347] [PMID: 35809639]
[3]
Pérez-Morales, R.E.; del Pino, M.D.; Valdivielso, J.M.; Ortiz, A.; Mora-Fernández, C.; Navarro-González, J.F. Inflammation in diabetic kidney disease. Nephron J., 2019, 143(1), 12-16.
[http://dx.doi.org/10.1159/000493278] [PMID: 30273931]
[4]
Hanouneh, M.; Echouffo Tcheugui, J.B.; Jaar, B.G. Recent advances in diabetic kidney disease. BMC Med., 2021, 19(1), 180.
[http://dx.doi.org/10.1186/s12916-021-02050-0] [PMID: 34399760]
[5]
Duan, J.; Wang, C.; Liu, D.; Qiao, Y.; Pan, S.; Jiang, D.; Zhao, Z.; Liang, L.; Tian, F.; Yu, P.; Zhang, Y.; Zhao, H.; Liu, Z. Prevalence and risk factors of chronic kidney disease and diabetic kidney disease in Chinese rural residents: A cross-sectional survey. Sci. Rep., 2019, 9(1), 10408.
[http://dx.doi.org/10.1038/s41598-019-46857-7] [PMID: 31320683]
[6]
Tomita, I.; Kume, S.; Sugahara, S.; Osawa, N.; Yamahara, K.; Yasuda-Yamahara, M.; Takeda, N.; Chin-Kanasaki, M.; Kaneko, T.; Mayoux, E.; Mark, M.; Yanagita, M.; Ogita, H.; Araki, S.; Maegawa, H. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab., 2020, 32(3), 404-419.e6.
[http://dx.doi.org/10.1016/j.cmet.2020.06.020] [PMID: 32726607]
[7]
Nissen, S.E.; Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med., 2007, 356(24), 2457-2471.
[http://dx.doi.org/10.1056/NEJMoa072761] [PMID: 17517853]
[8]
Ahmadian, M.; Suh, J.M.; Hah, N.; Liddle, C.; Atkins, A.R.; Downes, M.; Evans, R.M. PPARγ signaling and metabolism: The good, the bad and the future. Nat. Med., 2013, 19(5), 557-566.
[http://dx.doi.org/10.1038/nm.3159] [PMID: 23652116]
[9]
Wiseman, A.C. Kidney transplant options for the diabetic patient. Transplant. Rev., 2013, 27, 112-116.
[http://dx.doi.org/10.1007/s10571-009-9441-z] [PMID: 19711182]
[10]
Mousavi, S.H.; Tayarani, N.Z.; Parsaee, H. Protective effect of saffron extract and crocin on reactive oxygen species-mediated high glucose-induced toxicity in PC12 cells. Cell. Mol. Neurobiol., 2010, 30(2), 185-191.
[http://dx.doi.org/10.1007/s10571-009-9441-z] [PMID: 19711182]
[11]
Xing, B.; Li, S.; Yang, J.; Lin, D.; Feng, Y.; Lu, J.; Shao, Q. Phytochemistry, pharmacology, and potential clinical applications of saffron: A review. J. Ethnopharmacol., 2021, 281, 114555.
[http://dx.doi.org/10.1016/j.jep.2021.114555] [PMID: 34438035]
[12]
Karimi, E.; Shahdadian, F.; Hadi, A.; Tarrahi, M.A.; Tarrahi, M.J. The effect of saffron (Crocus sativus L.) supplementation on renal function: A systematic review and meta-analysis of randomized controlled clinical trials. Int. J. Clin. Pract., 2022, 2022, 1-10.
[http://dx.doi.org/10.1155/2022/9622546] [PMID: 36105788]
[13]
Hatziagapiou, K.; Lambrou, G.I. The protective role of Crocus sativus L. (Saffron) against ischemia- reperfusion injury, hyperlipidemia and atherosclerosis: Nature opposing cardiovascular diseases. Curr. Cardiol. Rev., 2018, 14(4), 272-289.
[http://dx.doi.org/10.2174/1573403X14666180628095918] [PMID: 29952263]
[14]
Ghaffari, S.; Roshanravan, N. Saffron; An updated review on biological properties with special focus on cardiovascular effects. Biomed. Pharmacother., 2019, 109, 21-27.
[http://dx.doi.org/10.1016/j.biopha.2018.10.031] [PMID: 30391705]
[15]
Zhang, L.; Jing, M.; Liu, Q. Crocin alleviates the inflammation and oxidative stress responses associated with diabetic nephropathy in rats via NLRP3 inflammasomes. Life Sci., 2021, 278, 119542.
[http://dx.doi.org/10.1016/j.lfs.2021.119542] [PMID: 33915128]
[16]
Zhang, J.; Zhao, X.; Zhu, H.; Wang, J.; Ma, J.; Gu, M. Crocin protects the renal tubular epithelial cells against high glucose-induced injury and oxidative stress via regulation of the SIRT1/Nrf2 pathway. Iran. J. Basic Med. Sci., 2022, 25(2), 193-197.
[PMID: 35655597]
[17]
Zhou, Y.; Xu, Q.; Shang, J.; Lu, L.; Chen, G. Crocin inhibits the migration, invasion, and epithelial‐mesenchymal transition of gastric cancer cells via miR‐320/KLF5/HIF‐1α signaling. J. Cell. Physiol., 2019, 234(10), 17876-17885.
[http://dx.doi.org/10.1002/jcp.28418] [PMID: 30851060]
[18]
Zhong, J.; Gong, W.; Lu, L.; Chen, J.; Lu, Z.; Li, H.; Liu, W.; Liu, Y.; Wang, M.; Hu, R.; Long, H.; Wei, L. Irbesartan ameliorates hyperlipidemia and liver steatosis in type 2 diabetic db/db mice via stimulating PPAR-γ AMPK/Akt/mTOR signaling and autophagy. Int. Immunopharmacol., 2017, 42, 176-184.
[http://dx.doi.org/10.1016/j.intimp.2016.11.015] [PMID: 27919004]
[19]
Abou-Hany, H.O.; Atef, H.; Said, E.; Elkashef, H.A.; Salem, H.A. Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats. Chem. Biol. Interact., 2018, 284, 90-100.
[http://dx.doi.org/10.1016/j.cbi.2018.02.001] [PMID: 29409856]
[20]
Huang, W.; Man, Y.; Gao, C.; Zhou, L.; Gu, J.; Xu, H.; Wan, Q.; Long, Y.; Chai, L.; Xu, Y.; Xu, Y. Short-chain fatty acids ameliorate diabetic nephropathy via gpr43-mediated inhibition of oxidative stress and NF-KB signaling. Oxid. Med. Cell. Longev., 2020, 2020, 1-21.
[http://dx.doi.org/10.1155/2020/8706898]
[21]
Ju, Y.; Su, Y.; Chen, Q.; Ma, K.; Ji, T.; Wang, Z.; Li, W.; Li, W. Protective effects of Astragaloside IV on endoplasmic reticulum stress-induced renal tubular epithelial cells apoptosis in type 2 diabetic nephropathy rats. Biomed. Pharmacother., 2019, 109, 84-92.
[http://dx.doi.org/10.1016/j.biopha.2018.10.041] [PMID: 30396095]
[22]
Huang, Y.; Liu, W.; Liu, J.; Guo, D.; Zhang, P.; Liu, D.; Lin, J.; Yang, L.; Zhang, H.; Xue, Y. Association of urinary sodium excretion and diabetic kidney disease in patients with type 2 diabetes mellitus: A cross-sectional study. Front. Endocrinol., 2021, 12, 772073.
[http://dx.doi.org/10.3389/fendo.2021.772073] [PMID: 34777262]
[23]
Parving, H.H.; Lehnert, H.; Bröchner-Mortensen, J.; Gomis, R.; Andersen, S.; Arner, P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N. Engl. J. Med., 2001, 345(12), 870-878.
[http://dx.doi.org/10.1056/NEJMoa011489] [PMID: 11565519]
[24]
Hu, R.; Wang, M.; Ni, S.; Wang, M.; Liu, L.; You, H.; Wu, X.; Wang, Y.; Lu, L.; Wei, L. Salidroside ameliorates endothelial inflammation and oxidative stress by regulating the AMPK/NF-κB/NLRP3 signaling pathway in AGEs-induced HUVECs. Eur. J. Pharmacol., 2020, 867, 172797.
[http://dx.doi.org/10.1016/j.ejphar.2019.172797] [PMID: 31747547]
[25]
Stieger, N.; Worthmann, K.; Teng, B.; Engeli, S.; Das, A.M.; Haller, H.; Schiffer, M. Impact of high glucose and transforming growth factor-β on bioenergetic profiles in podocytes. Metabolism, 2012, 61(8), 1073-1086.
[http://dx.doi.org/10.1016/j.metabol.2011.12.003] [PMID: 22365040]
[26]
Karunasagara, S.; Hong, G.L.; Park, S.R.; Lee, N.H.; Jung, D.Y.; Kim, T.W.; Jung, J.Y. Korean red ginseng attenuates hyperglycemia-induced renal inflammation and fibrosis via accelerated autophagy and protects against diabetic kidney disease. J. Ethnopharmacol., 2020, 254, 112693.
[http://dx.doi.org/10.1016/j.jep.2020.112693] [PMID: 32112899]
[27]
Qiao, S.; Liu, R.; Lv, C.; Miao, Y.; Yue, M.; Tao, Y.; Wei, Z.; Xia, Y.; Dai, Y. Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/β-TrcP/Nrf2 pathway. Free Radic. Biol. Med., 2019, 145, 118-135.
[http://dx.doi.org/10.1016/j.freeradbiomed.2019.09.003] [PMID: 31494242]
[28]
Ferre, T.; Pujol, A.; Riu, E.; Bosch, F.; Valera, A. Correction of diabetic alterations by glucokinase. Proc. Natl. Acad. Sci., 1996, 93(14), 7225-7230.
[http://dx.doi.org/10.1073/pnas.93.14.7225] [PMID: 8692973]
[29]
Hemmati, M.; Babaei, H.; Abdolsalehei, M. Survey of the effect of biotin on glycemic control and plasma lipid concentrations in type 1 diabetic patients in kermanshah in iran (2008-2009). Oman Med. J., 2013, 28(3), 195-198.
[http://dx.doi.org/10.5001/omj.2013.53] [PMID: 23772286]
[30]
Romero-Navarro, G.; Cabrera-Valladares, G.; German, M.S.; Matschinsky, F.M.; Velazquez, A.; Wang, J.; Fernandez-Mejia, C. Biotin regulation of pancreatic glucokinase and insulin in primary cultured rat islets and in biotin-deficient rats. Endocrinology, 1999, 140(10), 4595-4600.
[http://dx.doi.org/10.1210/endo.140.10.7084] [PMID: 10499515]
[31]
McCarty, M.F. In type 1 diabetics, high-dose biotin may compensate for low hepatic insulin exposure, promoting a more normal expression of glycolytic and gluconeogenic enyzymes and thereby aiding glycemic control. Med. Hypotheses, 2016, 95, 45-48.
[http://dx.doi.org/10.1016/j.mehy.2016.08.002] [PMID: 27692165]
[32]
Sahin, K.; Tuzcu, M.; Orhan, C.; Sahin, N.; Kucuk, O.; Ozercan, I.H.; Juturu, V.; Komorowski, J.R. Anti-diabetic activity of chromium picolinate and biotin in rats with type 2 diabetes induced by high-fat diet and streptozotocin. Br. J. Nutr., 2013, 110(2), 197-205.
[http://dx.doi.org/10.1017/S0007114512004850] [PMID: 23211098]
[33]
Sasaki, Y.; Sone, H.; Kamiyama, S.; Shimizu, M.; Shirakawa, H.; Kagawa, Y.; Komai, M.; Furukawa, Y. Administration of biotin prevents the development of insulin resistance in the skeletal muscles of Otsuka Long-Evans Tokushima fatty rats. Food Funct., 2012, 3(4), 414-419.
[http://dx.doi.org/10.1039/c2fo10175k] [PMID: 22218395]
[34]
Alam, M.M.; Iqbal, S.; Naseem, I. Ameliorative effect of riboflavin on hyperglycemia, oxidative stress and DNA damage in type-2 diabetic mice: Mechanistic and therapeutic strategies. Arch. Biochem. Biophys., 2015, 584, 10-19.
[http://dx.doi.org/10.1016/j.abb.2015.08.013] [PMID: 26319175]
[35]
Ashoori, M.; Saedisomeolia, A. Riboflavin (vitamin B2) and oxidative stress: A review. Br. J. Nutr., 2014, 111(11), 1985-1991.
[http://dx.doi.org/10.1017/S0007114514000178] [PMID: 24650639]
[36]
Wang, T.; Fu, X.; Chen, Q.; Patra, J.K.; Wang, D.; Wang, Z.; Gai, Z. Arachidonic acid metabolism and kidney inflammation. Int. J. Mol. Sci., 2019, 20(15), 3683.
[http://dx.doi.org/10.3390/ijms20153683] [PMID: 31357612]
[37]
Olearczyk, J.J.; Quigley, J.E.; Mitchell, B.C.; Yamamoto, T.; Kim, I.H.; Newman, J.W.; Luria, A.; Hammock, B.D.; Imig, J.D. Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats. Clin. Sci., 2009, 116(1), 61-70.
[http://dx.doi.org/10.1042/CS20080039] [PMID: 18459944]
[38]
Nieves, D.; Moreno, J.J. Epoxyeicosatrienoic acids induce growth inhibition and calpain/caspase-12 dependent apoptosis in PDGF cultured 3T6 fibroblast. Apoptosis, 2007, 12(11), 1979-1988.
[http://dx.doi.org/10.1007/s10495-007-0123-3] [PMID: 17828455]
[39]
Eid, S.; Maalouf, R.; Jaffa, A.A.; Nassif, J.; Hamdy, A.; Rashid, A.; Ziyadeh, F.N.; Eid, A.A. 20-HETE and EETs in diabetic nephropathy: A novel mechanistic pathway. PLoS One, 2013, 8(8), e70029.
[http://dx.doi.org/10.1371/journal.pone.0070029] [PMID: 23936373]
[40]
Liu, Y.; Zhang, Y.; Schmelzer, K.; Lee, T.S.; Fang, X.; Zhu, Y.; Spector, A.A.; Gill, S.; Morisseau, C.; Hammock, B.D.; Shyy, J.Y.J. The antiinflammatory effect of laminar flow: The role of PPARγ epoxyeicosatrienoic acids, and soluble epoxide hydrolase. Proc. Natl. Acad. Sci., 2005, 102(46), 16747-16752.
[http://dx.doi.org/10.1073/pnas.0508081102] [PMID: 16267130]
[41]
Schwartzman, M.L.; da Silva, J.L.; Lin, F.; Nishimura, M.; Abraham, N.G. Cytochrome P450 4A expression and arachidonic acid omega-hydroxylation in the kidney of the spontaneously hypertensive rat. Nephron J., 1996, 73(4), 652-663.
[http://dx.doi.org/10.1159/000189154] [PMID: 8856265]
[42]
Cowart, L.A.; Wei, S.; Hsu, M.H.; Johnson, E.F.; Krishna, M.U.; Falck, J.R.; Capdevila, J.H. The CYP4A isoforms hydroxylate epoxyeicosatrienoic acids to form high affinity peroxisome proliferator-activated receptor ligands. J. Biol. Chem., 2002, 277(38), 35105-35112.
[http://dx.doi.org/10.1074/jbc.M201575200] [PMID: 12124379]
[43]
Luo, P.; Zhou, Y.; Chang, H.H.; Zhang, J.; Seki, T.; Wang, C.Y.; Inscho, E.W.; Wang, M.H. Glomerular 20-HETE, EETs, and TGF-β1 in diabetic nephropathy. Am. J. Physiol. Renal Physiol., 2009, 296(3), F556-F563.
[http://dx.doi.org/10.1152/ajprenal.90613.2008] [PMID: 19129258]
[44]
Ciaramella, V.; Sasso, F.C.; Liello, R.D.; Corte, C.M.D.; Barra, G.; Viscardi, G.; Esposito, G.; Sparano, F.; Troiani, T.; Martinelli, E.; Orditura, M.; Vita, F.D.; Ciardiello, F.; Morgillo, F. Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC. J. Experi. Amp. Clin. Cancer Res., 2019, 38
[45]
Liu, L.; Pan, Y.; Zhai, C.; Zhu, Y.; Ke, R.; Shi, W.; Wang, J.; Yan, X.; Su, X.; Song, Y.; Gao, L.; Li, M. Activation of peroxisome proliferation-activated receptor‐γ inhibits transforming growth factor‐β1‐induced airway smooth muscle cell proliferation by suppressing Smad-miR‐21 signaling. J. Cell. Physiol., 2019, 234(1), 669-681.
[http://dx.doi.org/10.1002/jcp.26839] [PMID: 30132829]
[46]
Korman, B.; Marangoni, R.G.; Lord, G.; Olefsky, J.; Tourtellotte, W.; Varga, J. Adipocyte-specific repression of ppar-gamma by ncor contributes to scleroderma skin fibrosis; Arthritis Res. Amp: Thera, 2018, p. 20.
[47]
Liu, B.; Deng, C.; Tan, P. Ombuin ameliorates diabetic nephropathy in rats by anti‐inflammation and antifibrosis involving Notch 1 and PPAR γ signaling pathways. Drug Dev. Res., 2022, 83(6), 1270-1280.
[http://dx.doi.org/10.1002/ddr.21956] [PMID: 35672933]
[48]
Chen, X.; Sun, L.; Li, D.; Lai, X.; Wen, S.; Chen, R.; Zhang, Z.; Li, Q.; Sun, S. Green tea peptides ameliorate diabetic nephropathy by inhibiting the TGF-β/Smad signaling pathway in mice. Food Funct., 2022, 13(6), 3258-3270.
[http://dx.doi.org/10.1039/D1FO03615G] [PMID: 35234233]
[49]
Hayashi, H.; Abdollah, S.; Qiu, Y.; Cai, J.; Xu, Y.Y.; Grinnell, B.W.; Richardson, M.A.; Topper, J.N.; Gimbrone, M.A., Jr; Wrana, J.L.; Falb, D. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell, 1997, 89(7), 1165-1173.
[http://dx.doi.org/10.1016/S0092-8674(00)80303-7] [PMID: 9215638]
[50]
Zheng, W.; Qian, C.; Xu, F.; Cheng, P.; Yang, C.; Li, X.; Lu, Y.; Wang, A. Fuxin granules ameliorate diabetic nephropathy in db/db mice through tgf-b1/smad and VEGF/VEGFR2 signaling pathways. Biomed. Amp. Pharmacothera., 2021, 141, 111806.
[http://dx.doi.org/10.1016/j.biopha.2021.111806] [PMID: 34246190]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy