Resveratrolün sıçan diyabet modellerinde renal MMP-2 ve MMP-9 ekspresyonu üzerindeki düzenleyici etkileri

Diyabetes mellitusun neden olduğu hiperglisemiböbrek gibi hassas dokularda kan damarlarına zarar vererek işlev bozukluğuna neden olabilir. Matriks metaloproteinazlar (MMP'lar), özellikle MMP-2 ve MMP-9, proteinlerin bozunmasında ve anjiyojenezde önemli bir rol oynarken ;epidermal büyüme faktörü reseptörü (EGFR) hasarlı dokuların iyileşmesinde rol oynar.Burada streptozotosin ile indüklenmiş Wistar erkek sıçanların böbrek dokularında MMP-2 ve MMP-9/EGFR arasındaki ilişkiyi araştırdık. Ayrıcagüçlü doku koruyucu olarak bilinen resveratrolün bu değişiklikler üzerindeki etkilerini inceledik. Diyabet modeli streptozotosin (55 mg/kg) ile oluşturuldu ve tedavi için trans-resveratrol (20 mg/kg/gün intraperitoneal) kullanıldı. Sıçanlar kontrol, resveratrol (Res), diyabet (Diab) ve diyabet + resveratrol (Diab + Res) şeklinde 4 gruba ayrıldı. Diyabet grubundaki sıçanların böbreklerinde superoksitdismutaz(SOD)vekatalaz(CAT)düzeylerinin önemli ölçüde azaldığı buna karşınnitrit/nitrat, üre, kreatinin kinaz (CK) ve ürik asit konsantrasyonlarının arttığı saptanmıştır. Diyabet grubunda renal EGFR düzeyinin azalmasına rağmenMMP-2, MMP-9, kalsiyum bağlayan protein B (S100B)ve trombosit kaynaklı büyüme faktörü(PDGF)düzeyleri artmıştır. Resveratrol takviyesi tüm değişkenleri önemli ölçüde iyileştirdi. Diyabet, böbrek dokularındaki antioksidan enzimleri baskılayarak MMPile ilişkili inflamasyonu ve oksidatif stresi aktive eder. Resveratrol, diyabetin neden olduğu bu değişiklikler üzerinde kısmen modülatör etkilere sahiptir.

The regulatory effects of resveratrol on the expression of renal MMP-2 and MMP-9 in the rat models of diabetes

Hyperglycemia caused by diabetesmellitus, in sensitive tissues such as the kidney,can cause dysfunction by damaging the blood vessels. Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, play a significant role in the degradation of proteins and angiogenesis; while epidermal growth factor receptor (EGFR) is involved in the recovery of damaged tissues. Herein, we investigated the relationship between MMP-2 and MMP-9/EGFR in the kidney tissues of streptozotocin-induced Wistar male rats. We also examined the effects of resveratrol known as a strong tissue-protective on these changes. Diabetes was induced bystreptozotocin (55 mg/kg) and trans-resveratrol (20 mg/kg/day intraperitoneal) was used for treatment. Rats were divided into 4 groups as control, resveratrol (Res), diabetes (Diab)and diabetes plus resveratrol (Diab+Res). Superoxide dismutase (SOD) and catalase (CAT) levels were significantly decreased in the kidneys in the diabetic group, whereas nitrite/nitrate, urea, creatine kinase (CK) and uric acid concentrations increased. MMP-2, MMP-9, calcium-binding protein B (S100B)and platelet-derived growth factor (PDGF)concentrations of kidney were increased although reduced EGFR in the diabetes group. Resveratrol supplementation markedly restored all these structures. Diabetes activates MMP related inflammation and oxidative stress by suppressing antioxidant enzymes in the kidney tissues. Resveratrol has partly modulatory effects on diabetes-induced changes.

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  • Abdelgawad IY, Grant MKO, Zordoky BN (2019). Leveraging the cardio-protective and anticancer properties of resveratrol in cardio-oncology. Nutrients 11(3): 627.
  • Abderrahmani A, Yengo L, Caiazzo R, Canouil M, Cauchi S, Raverdy V, Plaisance V, Pawlowski V, Lobbens S, Maillet J, et al (2018). Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity-associated type 2 diabetes. Diabetes 67(7): 1310-1321.
  • Adlija JC, Maja M, Tanja D (2006). Creatine kinase activity in patients with diabetes mellitus type I and type II. Bosnian Journal of Basic Medical Sciences 6(3): 5-9.
  • Akar F, Pektas MB, Tufan C, Soylemez S, Sepici A, Ulus AT, Gokalp B, Ozturk K, Surucu HS (2011). Resveratrol shows vasoprotective effect reducing oxidative stress without affecting metabolic disturbances in insulin dependent diabetes of rabbits. Cardiovascular Drugs and Therapy 25(2): 119-131.
  • Alice C, Christian C, Josep M (2018). Resveratrol, metabolic syndrome, and gut microbiota. Nutrients 10(11): 1651.
  • Ankita S, Lokesh K, Thomas PJ, Kedar SP (2019). Targeting matrix metalloproteinases for diabetic retinopathy: The way ahead? Current Protein & Peptide Science 20(4): 324–333.
  • Babacanoglu C, Yildirim N, Sadi G, Pektas MB, Akar F (2013). Resveratrol prevents high-fructose corn syrup induced vascular insulin resistance and dysfunction in rats. Food and Chemical Toxicology 60: 160-167.
  • Bhatt JK, Thomas S, Nanjan MJ (2012). Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutrition Research 32(7): 537-541.
  • Chen J, Bai Q, Zhao Z, Sui H, Xie X (2016). Resveratrol improves delayed r-tPA treatment outcome by reducing MMPs. Acta Neurologica Scandinavica 134(1): 54-60.
  • Deng R, Mo F, Chang B, Zhang Q, Ran H, Yang S, Zhu Z, Hu L, Su Q (2017). Glucose-derived AGEs enhance human gastric cancer metastasis through RAGE/ERK/Sp1/MMP2 cascade. Oncotarget 8(61): 104216-104226.
  • Derosa G, D’angelo A, Tinelli C, Devangelio E, Consoli A, Miccoli R, Penno G, Del Prato S, Paniga S, Cicero AFG (2007). Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in diabetic and healthy subjects. Diabetes & Metabolism 33: 129-134.
  • Guglielmo S, Francesca R, Cataldo A, Claudia T, Roberta B, Ileana G, Rosario D (2013). S100B protein in tissue development, repair and regeneration. World Journal of Biological Chemistry 4(1): 1-12.
  • Jenifer K, Janaína K, Itiane F, Vivian N, Matheus DB, Cláudia GP, Nathana JM, Guilherme C, Luciane RF, Liana SF, et al (2019). Resveratrol and resveratrol-hydroxypropyl-β- cyclodextrin complex recovered the changes of creatine kinase and Na+, K+-ATPase activities found in the spleen from streptozotocin-induced diabetic rats. Anais da Academia Brasileira de Ciências 91(3): e20181330.
  • Jin X, Zimmers TA, Zhang Z, Koniaris LG (2019). Resveratrol improves recovery and survival of diet-induced obese mice undergoing extended major (80%) hepatectomy. Digestive Diseases and Sciences 64(1): 93-101.
  • Joshua JJ, Sherita HG (2014). Type 2 diabetes and cardiovascular disease: what next? Current Opinion in Endocrinology Diabetes and Obesity 21(2): 109-120.
  • Kadoglou NP, Daskalopoulou SS, Perrea D, Liapis CD (2005). Matrix metalloproteinases and diabetic vascular complications, Angiology 56(2): 173-189.
  • Katsanou P, Tentolouris N, Perrea D, Katsanos S, Ntova V, Antrian V, Konstantopoulos P, Politis A (2018). S100B levels in patients with type 2 diabetes mellitus and co-occurring depressive symptoms. Depression Research and Treatment 2018: 5304759.
  • Klein G, Vellenga E, Fraaije MW, Kampsa WA, de Bont ESJM (2004). The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia. Critical Reviews in Oncology/Hematology 50: 87-100.
  • Koca HB, Pektas MB, Koca S, Pektas G, Sadi G (2016). Diabetes-induced renal failure is associated with tissue inflammation and neutrophil gelatinase-associated lipocalin: Effects of resveratrol. Archives of Biological Sciences 68(4): 747-752.
  • Korkmaz OA, Sadi G, Kocabas A, Yildirim OG, Sumlu E, Koca HB, Nalbantoglu B, Pektas MB, Akar F (2019). Lactobacillus helveticus and Lactobacillus plantarum modulate renal antioxidant status in a rat model of fructose-induced metabolic syndrome. Archives of Biological Sciences 5: 1–8.
  • Kostov K, Blazhev A (2020). Use of glycated hemoglobin (A1c) as a biomarker for vascular risk in type 2 diabetes: Its relationship with matrix metalloproteinases-2, -9 and the metabolism of collagen IV and elastin. Medicina 56(5): 231.
  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951). Protein measurement with the Folin phenol reagent Journal of Biological Chemistry 193: 265-275.
  • Mahshad K, Fardin A, Ashraf M, Ladan K, Maryam SN, Azar P, Mojdeh B, Samaneh B, Aligholi S (2019). The modulating effects of Resveratrol on the expression of MMP-2 and MMP-9 in endometriosis women: a randomized exploratory trial. Gynecological Endocrinology 35(8): 719-726.
  • Melenhorst WB, Mulder GM, Xi Q, Joost GJ, Kimura K, Eguchi S, Goor H (2008). Epidermal growth factor receptor signaling in the kidney: key roles in physiology and disease. Hypertension 52(6): 987-993.
  • Miki M, Atutoshi K, Yutaka M, Kazumi Y (2011). Hypoglycemic effect of resveratrol in type 2 diabetic model db/db mice and its actions in cultured L6 myotubes and RIN-5F pancreatic β-cells. Journal of Clinical Biochemistry and Nutrition 48(3): 237-244.
  • Mohammadzadeh F, Tsoporis JN, Izhar S, Desjardins JF, Parker TG (2018). Deficiency of S100B confers resistance to experimental diabetes in mice. Experimental Cell Research 365(1): 129-137.
  • Naseer AS, Muhammad RK (2014). Antidiabetic effect of Sida cordata in alloxan induced diabetic rats. BioMed Research International 2014: 671294.
  • Ning C, Min H, Raouf AK (2017). Biochemical and biological attributes of matrix metalloproteinases. Progress in Molecular Biology and Translational Science 147: 1–73.
  • Pektas A, Sadi G, Pektas MB, Koca HB, Tosun M, Aslan E, Koca S (2017). Effects of resveratrol on diabetes induced vascular tissue damage and inflammation in male rats. Turkish Journal of Biochemistry 42(4): 451-458.
  • Pektas MB, Sadi G, Akar F (2015). Long-term dietary fructose causes gender-different metabolic and vascular dysfunction in rats: modulatory effects of resveratrol. Cellular Physiology and Biochemistry 37: 1407-1420.
  • Pektas MB, Sadi G, Koca HB, Yuksel Y, Vurmaz A, Koca T, Tosun M (2016a). Resveratrol ameliorates the components of hepatic inflammation and apoptosis in a rat model of streptozotocin-induced diabetes. Drug Development 77(1): 12-19.
  • Pektas MB, Koca HB, Sadi G, Akar F (2016b). Dietary fructose activates insulin signaling and inflammation in adipose tissue: Modulatory role of resveratrol. BioMed Research International 2016: 8014252.
  • Pektas MB, Yücel G, Koca HB, Sadi G, Yıldırım OG, Öztürk G, Akar F (2017). Dietary fructose-induced hepatic injury in male and female rats: Influence of resveratrol. Drug Research 67(2): 103-110.
  • Pektas MB, Turan O, Ozturk-Bingol G, Sumlu E, Sadi G, Akar F (2018). High glucose causes vascular dysfunction through Akt/eNOS pathway: reciprocal modulation by juglone and resveratrol. Canadian Journal of Biochemistry and Physiology. 96(8): 757-764.
  • Qian S, Zi-Ying S, Wei-Na D, Qing-Tao M, Zhong-Yuan X (2017). Mechanism of myocardial ischemia / reperfusion-induced acute kidney injury through DJ-1/Nrf2 pathway in diabetic rats. Experimental and Therapeutic Medicine 14(5): 4201-4207.
  • Renu AK, Manish M (2017). Regulation of matrix metalloproteinase in the pathogenesis of diabetic retinopathy. Progress in Molecular Biology and Translational Science 148: 67-85.
  • Sadi G, Baloglu MC, Pektas MB (2015). Differential gene expression in liver tissues of streptozotocin-induced diabetic rats in response to resveratrol treatment. PLoS One 2015; 10(4): e0124968.
  • Sadi G, Pektas MB, Koca HB, Tosun M, Koca T (2015). Resveratrol improves hepatic insulin signaling and reduces the inflammatory response in streptozotocin induced diabetes. Gene; 570(2): 213-220.
  • Sadi G, Şahin G, Bostancı A (2018). Modulation of renal insulin signaling pathway and antioxidant enzymes with streptozotocin- induced diabetes: Effects of resveratrol. Medicina; 55(3): 1-12.
  • Safrida S, Sabri M (2019). Effect of Muntingia calabura L. stem bark extracts on uric acid concentration and renal histopathology in diabetic rats. Medicina 55(10): 695.
  • Shan Z, Xu C, Wang W, Li W (2019). Enhanced PDGF signaling in gestational diabetes mellitus is involved in pancreatic β-cell dysfunction. Biochemical and Biophysical Research Communications 516(2): 402-407.
  • Signorelli SS, Malaponte G, Libra M, Di Pino L, Celotta G, Bevelacqua V, Petrina M, Nicotra GS, Indelicato M, Navolanic PM and et al (2005). Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease. Vascular Medicine 10(1): 1-6.
  • Sigrun G, Simon F, Alexandra A, Minoru T, Erika G, Reinhard F, Christer B (2004). Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131(8): 1847-1857.
  • Sreyashi M, Sayantan B, Sudipta R, Rinku S, Paramita G, Sanchita R, Syamsundar M, Samir B, Nabendu M (2016). Resveratrol alleviates cadmium-induced damage and overexpression of epidermal growth factor receptor and its downstream signaling proteins in the reproductive system of male Swiss albino mice. The Journal of Environmental Pathology, Toxicology, and Oncology 35(1): 73-90.
  • Taizo N, Hiroshi I, Masakiyo S (2012). Platelet-derived growth factor and renal disease. Current Opinion in Nephrology and Hypertension 21(1): 80- 85.
  • Talib AH, Thazhumpal CM, Ali AD, Sami A, Al-Zaid N, Hussein MD (2012). Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition 28(10): 1016-1021.
  • Thrailkill KM, Bunn C, Fowlkes JL (2009). Matrix metalloproteinases: their potential role in the pathogenesis of diabetic nephropathy. Endocrine 35(1): 1-10.
  • Togashi Y, Miyamoto Y (2013). Urinary cystatin C as a biomarker for diabetic nephropathy and its immunohistochemical localization in kidney in Zucker diabetic fatty (ZDF) rats. Experimental and Toxicologic Pathology 65(5): 615-622.
  • Wu L, Lan H, Jingying W, Fei Z, Zheng X, Haimin Y, Yuanyuan Q, Guang L, Chao Z, Yi W (2019). Inhibition of EGFR-STAT3 attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes. Journal of Endocrinology 242(3): 199-210.
  • Xue-Wen L, Hui-Ping C, Ying-Yan H, Wei-Li C, Jian-Wen C, Lu G, Hai-Yan H, Jun W (2018). Effects of rich-polyphenols extract of Dendrobium loddigesii on anti-diabetic, anti-inflammatory, anti-oxidant, and gut microbiota modulation in db/db mice. Molecules 23(12): 3245.
  • Yoshioka K, Takemura T, Murakami K, Akano N, Matsubara K, Aya N, Maki S (1990). Identification and localization of epidermal growth factor and its receptor in the human glomerulus. Laboratory Investigation 63(2): 189-196.
  • Yu H, Li H, Liu X, Du X, Deng B (2020). Levels of serum S100B are associated with cognitive dysfunction in patients with type 2 diabetes Aging 2020 12(5): 4193-4203.
  • Yuko T, Yohei M (2013). Urinary cystatin C as a biomarker for diabetic nephropathy and its immunohistochemical localization in kidney in Zucker diabetic fatty (ZDF) rats. Experimental and Toxicologic Pathology 65(5): 615-622.
  • Zeng-Mei A, Xing-Gang D, Yuan G, Jia-Liang Z, Tao Q (2015). Effects and clinical significance of pentoxifylline on the oxidative stress of rats with diabetic nephropathy. Huazhong University of Science and Technology Medical Sciences 35(3): 356-661.
  • Zhang M, Xue Y, Chen H, Meng L, Chen B, Gong H, Zhao Y, Qi R (2019). Resveratrol inhibits MMP3 and MMP9 expression and secretion by suppressing TLR4/NF- κ B/STAT3 activation in Ox-LDL-treated HUVECs oxid Oxidative Medicine and Cellular Longevity 2019: 9013169.
  • Zhu P, Ren M, Yang C, Hu YX, Ran JM, Yan L (2012). Involvement of RAGE, MAPK and NF-κB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes. Experimental Dermatology 21: 123-129.