A PDE1 Inhibitor, Vinpocetine, Ameliorates Epithelial-mesenchymal Transition and Renal Fibrosis in Adenine-induced Chronic Kidney Injury in Rats by Targeting the DNMT1/Klotho/β-catenin/Snail 1 and MMP-7 Pathways

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2024 Sep 14

PMID 39276250

Authors

Amira Mohammed Abdelfattah

Zeinab A Mohammed

Aliaa Talaat

Walaa Samy

Mamdouh Eldesoqui

Reham I Elgarhi

Affiliations

Soon will be listed here.

Abstract

Tubulointerstitial fibrosis (TIF) is present with chronic kidney disease (CKD). Vinpocetine (Vinpo) is used for treating cerebrovascular deficits, exhibiting some kidney-beneficial effects; however, its role in TIF is uncertain. So, the aim of this study was to investigate its potential impact on adenine-induced fibrotic CKD and explore the underlying mechanistic aspects. Eighteen male Wistar rats were categorized into three groups (n = 6 each). Group I was kept as controls and given saline; group II received adenine (300 mg/kg, twice weekly, i.p.) for induction of the CKD model; and group III was administered Vinpo (20 mg/kg/d, orally) concurrently with adenine. All treatments were administered for 4 weeks. Vinpo revealed an improvement in renal function and an alleviation of inflammation triggered by adenine via diminishing serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels. Further, Vinpo repressed the epithelial-mesenchymal transition (EMT) with preserved E-cadherin mRNA expression and lowered gene and immune expression of fibronectin and vimentin, respectively, besides attenuating the elevated G2/M arrest-related molecules (renal Ki67 protein contents and p21 gene expression). Renal pathological alterations caused by adenine were attenuated upon Vinpo administration. Interestingly, Vinpo suppressed abnormal renal β-catenin immunoreactivity, Snail 1, and MMP-7 gene expression while simultaneously restored Klotho protein expression by downregulating DNA methyltransferase 1 enzyme (DNMT1) protein expression in the kidney. These data indicated that Vinpo effectively mitigated EMT and G2/M arrest-induced renal fibrosis in adenine-induced CKD rats by targeting DNMT1-associated Klotho suppression, subsequently inhibiting β-catenin and its fibrotic downstream genes.

References

Amini N, Shoshtari M, Nejaddehbashi F, Dianat M, Badavi M . Dose-dependent renoprotective effect of vanillic acid on methotrexate-induced nephrotoxicity via its anti-apoptosis, antioxidant, and anti-inflammatory properties. Naunyn Schmiedebergs Arch Pharmacol. 2023; 397(6):4195-4204. DOI: 10.1007/s00210-023-02866-y. View

Ashour W, Zamzam M, Sayed Ali H, Ebrahim R . Effect of fetuin-A on adenine-induced chronic kidney disease model in male rats. Iran J Basic Med Sci. 2023; 26(5):511-516. PMC: 10083833. DOI: 10.22038/IJBMS.2023.66346.14584. View

Azouz A, Hersi F, Ali F, Hussein Elkelawy A, Omar H . Renoprotective effect of vinpocetine against ischemia/reperfusion injury: Modulation of NADPH oxidase/Nrf2, IKKβ/NF-κB p65, and cleaved caspase-3 expressions. J Biochem Mol Toxicol. 2022; 36(7):e23046. DOI: 10.1002/jbt.23046. View

Berger S, Kouzarides T, Shiekhattar R, Shilatifard A . An operational definition of epigenetics. Genes Dev. 2009; 23(7):781-3. PMC: 3959995. DOI: 10.1101/gad.1787609. View

Dhe-Paganon S, Syeda F, Park L . DNA methyl transferase 1: regulatory mechanisms and implications in health and disease. Int J Biochem Mol Biol. 2011; 2(1):58-66. PMC: 3180029. View

Diwan V, Brown L, Gobe G . Adenine-induced chronic kidney disease in rats. Nephrology (Carlton). 2017; 23(1):5-11. DOI: 10.1111/nep.13180. View

Elnfarawy A, Nashy A, Abozaid A, Komber I, Elweshahy R, Abdelrahman R . Vinpocetine attenuates thioacetamide-induced liver fibrosis in rats. Hum Exp Toxicol. 2020; 40(2):355-368. DOI: 10.1177/0960327120947453. View

Elwany N, Abdelhamid A, Mohamed N, Khalil S, Elsayed Orabi E, Abdelfattah A . Vinpocetine alleviates intestinal ischemia/reperfusion injury and enhances M2 macrophage polarization in rats: Role of SIRT1/SOCS3/STAT3 signaling pathway. Int Immunopharmacol. 2023; 122:110654. DOI: 10.1016/j.intimp.2023.110654. View

Fattori V, Borghi S, Guazelli C, Giroldo A, Crespigio J, Bussmann A . Vinpocetine reduces diclofenac-induced acute kidney injury through inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB activation in mice. Pharmacol Res. 2017; 120:10-22. DOI: 10.1016/j.phrs.2016.12.039. View

10.

FAWCETT J, Scott J . A rapid and precise method for the determination of urea. J Clin Pathol. 1960; 13:156-9. PMC: 480024. DOI: 10.1136/jcp.13.2.156. View

11.

Feiteng C, Lei C, Deng L, Chaoliang X, Zijie X, Yi S . Relaxin inhibits renal fibrosis and the epithelial-to-mesenchymal transition via the Wnt/β-catenin signaling pathway. Ren Fail. 2022; 44(1):513-524. PMC: 8942541. DOI: 10.1080/0886022X.2022.2044351. View

12.

Hayeeawaema F, Muangnil P, Jiangsakul J, Tipbunjong C, Huipao N, Khuituan P . A novel model of adenine-induced chronic kidney disease-associated gastrointestinal dysfunction in mice: The gut-kidney axis. Saudi J Biol Sci. 2023; 30(6):103660. PMC: 10193294. DOI: 10.1016/j.sjbs.2023.103660. View

13.

Hsu S, RAINE L, FANGER H . Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981; 29(4):577-80. DOI: 10.1177/29.4.6166661. View

14.

Hu L, Ding M, He W . Emerging Therapeutic Strategies for Attenuating Tubular EMT and Kidney Fibrosis by Targeting Wnt/β-Catenin Signaling. Front Pharmacol. 2022; 12:830340. PMC: 8784548. DOI: 10.3389/fphar.2021.830340. View

15.

Iwano M, Plieth D, Danoff T, Xue C, Okada H, Neilson E . Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002; 110(3):341-50. PMC: 151091. DOI: 10.1172/JCI15518. View

16.

Jurikova M, Danihel L, Polak S, Varga I . Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. Acta Histochem. 2016; 118(5):544-52. DOI: 10.1016/j.acthis.2016.05.002. View

17.

Kadatane S, Satariano M, Massey M, Mongan K, Raina R . The Role of Inflammation in CKD. Cells. 2023; 12(12). PMC: 10296717. DOI: 10.3390/cells12121581. View

18.

Kim K, Dunn C, Park K . Recent progress in mapping the emerging landscape of the small-cell lung cancer genome. Exp Mol Med. 2019; 51(12):1-13. PMC: 6906379. DOI: 10.1038/s12276-019-0349-5. View

19.

La L, Wang L, Qin F, Jiang J, He S, Wang C . Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats: regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. J Ethnopharmacol. 2017; 219:81-90. DOI: 10.1016/j.jep.2017.12.013. View

20.

Li S, He A, Deng Z, Liu Q . Ginsenoside-Rg1 Protects against Renal Fibrosis by Regulating the Klotho/TGF-β1/Smad Signaling Pathway in Rats with Obstructive Nephropathy. Biol Pharm Bull. 2018; 41(4):585-591. DOI: 10.1248/bpb.b17-00934. View