Ameliorative effect of melatonin against increased intestinal permeability in diabetic rats: possible involvement of MLCK-dependent MLC phosphorylation
The increased intestinal permeability and functional impairment play an important role in type 2 diabetes (T2D), and melatonin may possess enteroprotection properties. Therefore, we used streptozotocin-induced diabetic rat model to investigate the regulation of intestinal permeability by melatonin. Rats were randomly divided into three groups, including control, diabetes mellitus (DM), and DM rats treated with melatonin. Melatonin was administered (10 mg/kg/day) by gavage for 24 weeks. The DM rats significantly increased the serum fasting blood glucose and lipid levels, which were alleviated by melatonin treatment. Importantly, the intestinal epithelial permeability was significantly increased in DM rats but was ameliorated following treatment with melatonin. These findings also indicated the expression of myosin light chain kinase (MLCK) and phosphorylation of MLC targeting subunit (MYPT) induced myosin light chain (MLC) phosphorylation level was markedly elevated in hyperglycemic and hyperlipidemic status. They were partly associated with down-regulated membrane type 1 and 2 (MT1 and MT2) expression, and up-regulated Rho-associated protein kinase (ROCK) expression and increased extracellular signal-regulated kinase (ERK) phosphorylation. However, the changes in target protein expression were reversed by melatonin. In conclusion, our results show melatonin beneficial effects on impaired intestinal epithelial permeability in T2D by suppressing ERK/MLCK- and ROCK/MCLP-dependent MLC phosphorylation.
KeywordsDiabetes Intestinal epithelial permeability Melatonin Myosin light chain kinase
This study was supported by the National Nature Science Research Grants (Nos.: 81272399, 81470568), Fund of colleges excellent young key projects in Anhui Province (No. 2013SQRL101ZD), and the Anhui Natural Science Foundation (No. 1508085QH167), Doctor fund of Anhui Medical University (No. 0108020103).
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 6.Sapone A, de Magistris L, Pietzak M, Clemente MG, Tripathi A, Cucca F, Lampis R, Kryszak D, Carteni M, Generoso M, Iafusco D, Prisco F, Laghi F, Riegler G, Carratu R, Counts D, Fasano A (2006) Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55:1443–1449CrossRefPubMedGoogle Scholar
- 15.Clayburgh DR, Barrett TA, Tang Y, Meddings JB, Van Eldik LJ, Watterson DM, Clarke LL, Mrsny RJ, Turner JR (2005) Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J Clin Invest 115:2702–2715CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Chu J, Miller CT, Kislitsyna K, Laine GA, Stewart RH, Cox CS, Uray KS (2012) Decreased myosin phosphatase target subunit 1(MYPT1) phosphorylation via attenuated rho kinase and zipper-interacting kinase activities in edematous intestinal smooth muscle. Neurogastroenterol Motil 24:257–266CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Tang ST, Su H, Zhang Q, Tang HQ, Wang CJ, Zhou Q, Wei W, Zhu HQ, Wang Y (2015) Melatonin attenuates aortic endothelial permeability and arteriosclerosis in streptozotocin-induced diabetic rats: possible role of MLCK- and MLCP-dependent MLC phosphorylation. J Cardiovasc Pharmacol Ther 21:82–92CrossRefPubMedGoogle Scholar
- 25.Paredes SD, Terrón MP, Marchena AM, Barriga C, Pariente JA, Reiter RJ, Rodríguez AB (2007) Effect of exogenous melatonin on viability, ingestion capacity, and free-radical scavenging in heterophils from young and old ringdoves (Streptopelia risoria). Mol Cell Biochem 304:305–314CrossRefPubMedGoogle Scholar
- 34.Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European prospective investigation into cancer and nutrition (EPIC)-potsdam study. Diabetes 52:812–817CrossRefPubMedGoogle Scholar
- 42.Jayashree B, Bibin YS, Prabhu D, Shanthirani CS, Gokulakrishnan K, Lakshmi BS, Mohan V, Balasubramanyam M (2014) Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of pro-inflammation in patients with type 2 diabetes. Mol Cell Biochem 388:203–210CrossRefPubMedGoogle Scholar
- 46.Buendia I, Navarro E, Michalska P, Gameiro I, Egea J, Abril S, López A, González-Lafuente L, López MG, León R (2015) New melatonin-cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection. Future Med Chem 7:1961–1969CrossRefPubMedGoogle Scholar
- 51.Swanson GR, Gorenz A, Shaikh M, Desai V, Forsyth C, Fogg L, Burgess HJ, Keshavarzian A (2015) Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics. Am J Physiol Gastrointest Liver Physiol 308:G1004–G1011CrossRefPubMedGoogle Scholar