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

Overview

Journal Curr Drug Metab

Publisher Bentham Science Publishers

Specialties Chemistry
Endocrinology

Date 2023 Nov 8

PMID 37936469

Authors

Wei Chen

Jinhao Su

Yubin Liu

Tianmei Gao

Xiaohui Ji

Hanzhou Li

Huajun Li

Yuansong Wang

Hui Zhang

Shuquan Lv

Affiliations

Soon will be listed here.

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.

References

Ferre T, Pujol A, Riu E, Bosch F, Valera A . Correction of diabetic alterations by glucokinase. Proc Natl Acad Sci U S A. 1996; 93(14):7225-30. PMC: 38964. DOI: 10.1073/pnas.93.14.7225. View

Eid S, Maalouf R, Jaffa A, Nassif J, Hamdy A, Rashid A . 20-HETE and EETs in diabetic nephropathy: a novel mechanistic pathway. PLoS One. 2013; 8(8):e70029. PMC: 3732284. DOI: 10.1371/journal.pone.0070029. View

German M, Matschinsky F, 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):4595-600. DOI: 10.1210/endo.140.10.7084. View

Cowart L, Wei S, Hsu M, Johnson E, Krishna M, Falck J . The CYP4A isoforms hydroxylate epoxyeicosatrienoic acids to form high affinity peroxisome proliferator-activated receptor ligands. J Biol Chem. 2002; 277(38):35105-12. DOI: 10.1074/jbc.M201575200. View

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. PMC: 9124533. DOI: 10.22038/IJBMS.2022.51597.11708. View

Nieves D, Moreno J . Epoxyeicosatrienoic acids induce growth inhibition and calpain/caspase-12 dependent apoptosis in PDGF cultured 3T6 fibroblast. Apoptosis. 2007; 12(11):1979-88. DOI: 10.1007/s10495-007-0123-3. View

Hu R, Wang M, Ni S, Wang M, Liu L, You H . Salidroside ameliorates endothelial inflammation and oxidative stress by regulating the AMPK/NF-κB/NLRP3 signaling pathway in AGEs-induced HUVECs. Eur J Pharmacol. 2019; 867:172797. DOI: 10.1016/j.ejphar.2019.172797. View

Huang W, Man Y, Gao C, Zhou L, Gu J, Xu H . Short-Chain Fatty Acids Ameliorate Diabetic Nephropathy via GPR43-Mediated Inhibition of Oxidative Stress and NF-B Signaling. Oxid Med Cell Longev. 2020; 2020:4074832. PMC: 7422068. DOI: 10.1155/2020/4074832. View

Liu L, Pan Y, Zhai C, Zhu Y, Ke R, Shi W . 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. 2018; 234(1):669-681. DOI: 10.1002/jcp.26839. View

10.

Wang T, Fu X, Chen Q, Patra J, Wang D, Wang Z . Arachidonic Acid Metabolism and Kidney Inflammation. Int J Mol Sci. 2019; 20(15). PMC: 6695795. DOI: 10.3390/ijms20153683. View

11.

Stieger N, Worthmann K, Teng B, Engeli S, Das A, Haller H . Impact of high glucose and transforming growth factor-β on bioenergetic profiles in podocytes. Metabolism. 2012; 61(8):1073-86. DOI: 10.1016/j.metabol.2011.12.003. View

12.

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. DOI: 10.1002/ddr.21956. View

13.

Ju Y, Su Y, Chen Q, Ma K, Ji T, Wang Z . Protective effects of Astragaloside IV on endoplasmic reticulum stress-induced renal tubular epithelial cells apoptosis in type 2 diabetic nephropathy rats. Biomed Pharmacother. 2018; 109:84-92. DOI: 10.1016/j.biopha.2018.10.041. View

14.

Hayashi H, Abdollah S, Qiu Y, Cai J, Xu Y, Grinnell B . The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997; 89(7):1165-73. DOI: 10.1016/s0092-8674(00)80303-7. View

15.

Yuan S, Wang Y, Li Z, Chen X, Song P, Chen A . 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. DOI: 10.1016/j.abb.2022.109347. View

16.

Schwartzman M, Da Silva J, Lin F, Nishimura M, Abraham N . Cytochrome P450 4A expression and arachidonic acid omega-hydroxylation in the kidney of the spontaneously hypertensive rat. Nephron. 1996; 73(4):652-63. DOI: 10.1159/000189154. View

17.

Xiang E, Han B, Zhang Q, Rao W, Wang Z, Chang C . Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis. Stem Cell Res Ther. 2020; 11(1):336. PMC: 7397631. DOI: 10.1186/s13287-020-01852-y. View

18.

Wiseman A . Kidney transplant options for the diabetic patient. Transplant Rev (Orlando). 2013; 27(4):112-6. DOI: 10.1016/j.trre.2013.07.002. View

19.

Ciaramella V, Sasso F, Di Liello R, Della Corte C, Barra G, Viscardi G . Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC. J Exp Clin Cancer Res. 2019; 38(1):178. PMC: 6485164. DOI: 10.1186/s13046-019-1176-1. View

20.

McCarty M . 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. DOI: 10.1016/j.mehy.2016.08.002. View