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01-12-2019 | Diabetic Nephropathy | Original Article

Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism

Authors: Sucai Song, Minyan Dang, Mukresh Kumar

Published in: Inflammopharmacology | Issue 6/2019

Abstract

P38 mitogen-activated protein kinase (p38 MAPK), a tissue inflammatory factor can be activated under oxidative stress and in conditions associated with hyperglycemia. Gingerol containing various natural herbs has been extensively studied for its pharmacological actions both in reducing the inflammation and as immunity booster. The aim of the current investigation was to examine the renal protective effect of gingerol in high-fat diet/streptozotocin-induced type II diabetes mellitus in a rat model.NRK 52E cells were divided into normal and high glucose group treated with gingerol. The methylthiazotetrazolium assay was used to establish the cell proliferation progress. Streptozotocin-inducted diabetes in rats was treated with gingerol for 16 weeks. The blood glucose, serum creatinine, body weight, food intake, biochemical, antioxidant and haematological parameters were assayed to establish the correlation. Pro-inflammatory cytokines including Il-1β, IL-6, TNF-α; inflammatory mediator COX-2, PGE₂, NF-kB, p38MAPK, and TGF-β, were also determined to assess the molecular mechanism. Gingerol exhibited the protective effect on the high glucose level induced NRK 52E cells and did not show any effect on the normal cells. Gingerol significantly (P < 0.001) down-regulated the blood glucose level, creatinine and BUN level in a dose-dependent manner with further significantly (P < 0.001) alteration in pro-inflammatory cytokines, nuclear factor kappa B (N-κB) activation, renal p38MAPK, and TGF-β. From these studies it is possible to predict that gingerol plays a significant role in improving the condition of renal tissue by alteration in p38MAPK and NF-κB activity, and control inflammatory reaction and oxidative stress. Our investigation supports the clinical use of gingerol in future as an effective renal protective agent.

Ahmed D, Kumar V, Verma A et al (2015) Antidiabetic, antioxidant, antihyperlipidemic effect of extract of Euryale ferox salisb. with enhanced histopathology of pancreas, liver and kidney in streptozotocin induced diabetic rats. Springerplus 4:315. https://doi.org/10.1186/s40064-015-1059-7 CrossRefPubMedPubMedCentral

Barrientos S, Stojadinovic O, Golinko MS et al (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16(5):585–601. https://doi.org/10.1111/j.1524-475x.2008.00410.x CrossRefPubMed

Bianchi G, Martella R, Ravera S et al (2015) Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models. Oncotarget 6(14):11806–11819. https://doi.org/10.18632/oncotarget.3688 CrossRefPubMedPubMedCentral

Blanca AJ, Ruiz-Armenta MV, Zambrano S et al (2017) L-Carnitine ameliorates the oxidative stress response to angiotensin II by modulating NADPH oxidase through a reduction in protein kinase c activity and NF-κB translocation to the nucleus. Food Chem 228:356–366. https://doi.org/10.1016/j.foodchem.2017.02.011 CrossRefPubMed

Bradford MM (1976) A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Anal Biochem 72:248–254CrossRefPubMed

Chun CT, Nica AF, Kurinna SM et al (2007) Mitochondrial protein phosphatase 2A regulates cell death induced by simulated ischemia in kidney NRK-52E cells. Cell Cycle 6(19):2377–2385. https://doi.org/10.4161/cc.6.19.4737 CrossRef

Couser WG (1998) Pathogenesis of glomerular damage in glomerulonephritis. Nephrol Dial Transpl 13(Suppl 1):10–15. https://doi.org/10.1177/0194599817696308 CrossRef

Donate-Correa J, Martín-Núñez E, Muros-De-Fuentes M et al (2015) Inflammatory cytokines in diabetic nephropathy. J Diabetes Res. https://doi.org/10.1155/2015/948417 CrossRefPubMedPubMedCentral

Dugasani S, Pichika MR, Nadarajah VD et al (2010) Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J Ethnopharmacol 127:515–520. https://doi.org/10.1016/j.jep.2009.10.004 CrossRefPubMed

Everard A, Lazarevic V, Derrien M et al (2011) Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60(11):2775–2786. https://doi.org/10.2337/db11-0227 CrossRefPubMedPubMedCentral

Geng Y, Chandrasekaran S, Hsu JW et al (2013) Phenotypic switch in blood: effects of pro-inflammatory cytokines on breast cancer cell aggregation and adhesion. PLoS ONE. https://doi.org/10.1371/journal.pone.0054959 CrossRefPubMedPubMedCentral

Griffin SV (2003) Podocyte proliferation and differentiation in glomerular disease: role of cell-cycle regulatory proteins. Nephrol Dial Transpl 18(6):vi8–vi13. https://doi.org/10.1093/ndt/gfg1069 CrossRef

Hartono SP, Grande JP (2014) Tubulointerstitial injury: signaling pathways, inflammation, fibrogenesis. Renal Vasc Dis. https://doi.org/10.1007/978-1-4471-2810-6_10 CrossRef

He C, Sabol J, Mitsuhashi T, Vlassara H (2000) Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes 48:1308–1315. https://doi.org/10.2337/diabetes.48.6.1308 CrossRef

Hsieh P, Liu SF, Lee TC et al (2012) The role of IL-7 in renal proximal tubule epithelial cells fibrosis. Mol Immunol 50(1–2):74–82. https://doi.org/10.1016/j.molimm.2011.12.004 CrossRefPubMed

Huang THW, Teoh AW, Lin BL et al (2009) The role of herbal PPAR modulators in the treatment of cardiometabolic syndrome. Pharmacol Res 60(3):195–206. https://doi.org/10.1016/j.phrs.2009.03.020 CrossRefPubMed

Janssen B, Hohenadel D, Brinkkoetter P et al (2005) Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 54:2320–2327. https://doi.org/10.2337/diabetes.54.8.2320 CrossRefPubMed

Johnson MD, Reeder JE, O’Connell M (2016) P38MAPK activation and DUSP10 expression in meningiomas. J Clin Neurosci 30:110–114. https://doi.org/10.1016/j.jocn.2015.12.031 CrossRefPubMed

Kifayatullah M, Mustafa MS, Sengupta P et al (2015) Evaluation of the acute and sub-acute toxicity of the ethanolic extract of Pericampylus glaucus (Lam.) Merr. in BALB/c mice. J Acute Dis 4:309–315. https://doi.org/10.1016/j.joad.2015.06.010 CrossRef

Kosla J, Dvorakova M, Dvorak M, Cermak V (2013) Effective myofibroblast dedifferentiation by concomitant inhibition of TGF-β signaling and perturbation of MAPK signaling. Eur J Cell Biol 92(12):363–373. https://doi.org/10.1016/j.ejcb.2013.10.013 CrossRefPubMed

Kumar V, Ahmed D, Gupta PS et al (2013) Anti-diabetic, anti-oxidant and anti-hyperlipidemic activities of Melastoma malabathricum Linn. leaves in streptozotocin induced diabetic rats. BMC Complement Altern Med 13:222. https://doi.org/10.1186/1472-6882-13-222 CrossRefPubMedPubMedCentral

Lan HY, Chung ACK (2012) TGF-β/smad signaling in kidney disease. Semin Nephrol 32:236–243. https://doi.org/10.1016/j.semnephrol.2012.04.002 CrossRefPubMed

Li Z, Huylebroeck D, Chen Y-G (2013) TGF-β signaling in stem cell fate determination. TGF-β Hum Dis. https://doi.org/10.1007/978-4-431-54409-8_2 CrossRef

Li SS, Liu QF, He AL, Wu FR (2014) Tranilast attenuates TGF-β1-induced epithelial-mesenchymal transition in the NRK-52E cells. Pak J Pharm Sci 27(1):51–55PubMed

Li C, Miao X, Li F et al (2017) Oxidative stress-related mechanisms and antioxidant therapy in diabetic retinopathy. Oxid Med Cell Longev. https://doi.org/10.1155/2017/9702820 CrossRefPubMedPubMedCentral

Liu H, Peng Y, Liu F et al (2008) Renal function and serum albumin at the start of dialysis in 514 Chinese ESRD in-patients. Ren Fail 30(7):685–690. https://doi.org/10.1080/08860220802212619 CrossRefPubMed

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔCT) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262 CrossRefPubMed

Marshall CB, Shankland SJ (2006) Cell cycle and glomerular disease: a minireview. Nephron Exp Nephrol 102(2):e39–e48. https://doi.org/10.1159/000088400 CrossRefPubMed

Marumo T, Hishikawa K, Yoshikawa M et al (2010) Histone deacetylase modulates the proinflammatory and -fibrotic changes in tubulointerstitial injury. Am J Physiol Ren Physiol 298:F133–F141. https://doi.org/10.1152/ajprenal.00400.2009 CrossRef

Nakayama T, Kosugi T, Gersch M et al (2010) Dietary fructose causes tubulointerstitial injury in the normal rat kidney. AJP Ren Physiol 298:F712–F720. https://doi.org/10.1152/ajprenal.00433.2009 CrossRef

Onkaramurthy M, Veerapur VP, Thippeswamy BS et al (2013) Anti-diabetic and anti-cataract effects of Chromolaena odorata Linn., in streptozotocin-induced diabetic rats. J Ethnopharmacol 145:363–372. https://doi.org/10.1016/j.jep.2012.11.023 CrossRefPubMed

Pospisilik JA, Martin J, Doty T et al (2003) Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes 52(3):741–750CrossRefPubMed

Qing Q, Zhang S, Chen Y et al (2015) High glucose-induced intestinal epithelial barrier damage is aggravated by syndecan-1 destruction and heparanase overexpression. J Cell Mol Med 19(6):1366–1374. https://doi.org/10.1111/jcmm.12523 CrossRefPubMedPubMedCentral

Remy G, Risco AM, Iñesta-Vaquera FA et al (2010) Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal 22(4):660–667. https://doi.org/10.1016/j.cellsig.2009.11.020 CrossRefPubMed

Rodríguez-García ME, Quiroga AG, Castro J et al (2009) Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells. Toxicol Sci 111(2):413–423. https://doi.org/10.1093/toxsci/kfp145 CrossRefPubMed

Ruiz-Ortega M, Rodríguez-Vita J, Sanchez-Lopez E et al (2007) TGF-β signaling in vascular fibrosis. Cardiovasc Res 74(2):196–206. https://doi.org/10.1016/j.cardiores.2007.02.008 CrossRefPubMed

Sadar S, Kaspate D, Vyawahare N (2016) Protective effect of l-glutamine against diabetes-induced nephropathy in experimental animal: role of KIM-1, NGAL, TGF-β1, and collagen-1. Ren Fail 38:1483–1495. https://doi.org/10.1080/0886022x.2016.1227918 CrossRefPubMed

Safavi SM, Kazemi B, Esmaeili M et al (2008) Effects of low-level He–Ne laser irradiation on the gene expression of IL-1β, TNF-α, IFN-γ, TGF-β, bFGF, and PDGF in rat’s gingiva. Lasers Med Sci 23(3):331–335. https://doi.org/10.1007/s10103-007-0491-5 CrossRefPubMed

Schleicher ED, Weigert C (2000) Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int 77:S13–S18. https://doi.org/10.1046/j.1523-1755.2000.07703.x CrossRef

Spranger J, Kroke A, Möhlig M et al (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 52:812–817. https://doi.org/10.2337/diabetes.52.3.812 CrossRefPubMed

Sun M, Paciga JE, Feldman RI et al (2001) Phosphatidylinositol-3-OH kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor α (ERα) via interaction between ERα and PI3K. Cancer Res 61:5985–5991. https://doi.org/10.1038/nature CrossRefPubMed

Wallin M, Sallsten G, Lundh T, Barregard L (2014) Low-level cadmium exposure and effects on kidney function. Occup Environ Med 71(12):848–854. https://doi.org/10.1136/oemed-2014-102279 CrossRefPubMed

Walum E (1998) Acute oral toxicity. Environ Health Perspect 106(Suppl 2):497–503. https://doi.org/10.1289/ehp.98106497 CrossRefPubMedPubMedCentral

Wang W, Koka V, Lan HY (2005) Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrol. 10(1):48–56. https://doi.org/10.1111/j.1440-1797.2005.00334.x CrossRef

Wang Y, Zhang Y, Sun B et al (2017) Rutin protects against pirarubicin-induced cardiotoxicity through TGF-β 1-p38 MAPK signaling pathway. Evid Based Complement Altern Med. https://doi.org/10.1155/2017/1759385 CrossRef

Yamamoto T, Nakamura T, Noble NA et al (1993) Expression of transforming growth factor 18 is elevated in human and experimental diabetic nephropathy (diabetes mellitus/kidney disease/extracellular matrix). Proc Natl Acad Sci 90(5):1814–1818CrossRefPubMedPubMedCentral

Zhang Y, Li H, Zhu J et al (2017) Role of artesunate in TGF-β1-induced renal tubular epithelial-mesenchymal transdifferentiation in NRK-52E cells. Mol Med Rep 16:8891–8899. https://doi.org/10.3892/mmr.2017.7728 CrossRefPubMedPubMedCentral

Ziyadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4(1):39–45. https://doi.org/10.2174/157339908783502370 CrossRefPubMed

Zoja C, Zanchi C, Benigni A (2015) Key pathways in renal disease progression of experimental diabetes. Nephrol Dial Transplant 30(4):iv54–iv59. https://doi.org/10.1093/ndt/gfv036 CrossRefPubMed

Title: Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism
Authors: Sucai Song
Minyan Dang
Mukresh Kumar
Publication date: 01-12-2019
Publisher: Springer International Publishing
Keywords: Diabetic Nephropathy
Cytokines
Published in: Inflammopharmacology / Issue 6/2019
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-019-00569-6

At a glance: The STEP trials

Springer Medicine

Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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