Rutin Prevents High Glucose-Induced Renal Glomerular Endothelial Hyperpermeability by Inhibiting the ROS/Rhoa/ROCK Signaling Pathway

 

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Abstract

Diabetic nephropathy is a progressive kidney disease caused by damage to the capillaries in the glomeruli. Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy. Hyperglycemia-induced endothelial hyperpermeability is crucial to diabetic nephropathy. Rutin has beneficial effects on diabetic nephropathy, but the exact mechanisms of its protective effect remain elusive. The aim of this study was to assess the role of pretreatment with rutin in an in vitro model of hyperglycemia-induced barrier dysfunction in human renal glomerular endothelial cells. Human renal glomerular endothelial cells were exposed to rutin and/or hyperglycemia for 24 h. Hyperglycemia increased permeability and decreased the junction protein occludin in the cell-cell junction area and the total expression in human renal glomerular endothelial cells, whereas rutin treatment significantly corrected these abnormalities. Furthermore, hyperglycemia-induced activation of RhoA/ROCK was reversed by treatment with rutin or the knockdown of ROCK2. Interestingly, rutin prevented hyperglycemia-induced hyperpermeability, and dysfunction of the tight junction, a high level of reactive oxygen species, and activation of RhoA/ROCK were significantly abolished with the knockdown of Nrf2. In conclusion, rutin significantly prevented hyperglycemia-disrupted renal endothelial barrier function by inhibiting the RhoA/ROCK signaling pathway through decreasing reactive oxygen species, which was mediated by the activation of Nrf2. Our results may explain, at least in part, some beneficial effects of rutin that may be applicable to the treatment of vascular disorders in diabetic nephropathy.

• References

• 1 Haraldsson B, Nystrom J. The glomerular endothelium: new insights on function and structure. Curr Opin Nephrol Hypertens 2012; 21: 258-263
  CrossrefPubMedGoogle Scholar
• 2 Sward P, Rippe B. Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability. Acta Physiol (Oxf) 2012; 204: 294-307
  CrossrefPubMedGoogle Scholar
• 3 Fu J, Lee K, Chuang PY, Liu Z, He JC. Glomerular endothelial cell injury and cross talk in diabetic kidney disease. Am J Physiol Renal Physiol 2015; 308: F287-F297
  CrossrefPubMedGoogle Scholar
• 4 Luo P, Peng H, Li C, Ye Z, Tang H, Tang Y, Chen C, Lou T. Advanced glycation end products induce glomerular endothelial cell hyperpermeability by upregulating matrix metalloproteinase activity. Mol Med Rep 2015; 11: 4447-4453
  PubMedGoogle Scholar
• 5 Peng H, Luo P, Li Y, Wang C, Liu X, Ye Z, Li C, Lou T. Simvastatin alleviates hyperpermeability of glomerular endothelial cells in early-stage diabetic nephropathy by inhibition of RhoA/ROCK1. PLoS One 2013; 8: e80009
  CrossrefPubMedGoogle Scholar
• 6 Friden V, Oveland E, Tenstad O, Ebefors K, Nystrom J, Nilsson UA, Haraldsson B. The glomerular endothelial cell coat is essential for glomerular filtration. Kidney Int 2011; 79: 1322-1330
  CrossrefPubMedGoogle Scholar
• 7 Wang F, Pu C, Zhou P, Wang P, Liang D, Wang Q, Hu Y, Li B, Hao X. Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2. Cell Physiol Biochem 2015; 36: 315-324
  CrossrefPubMedGoogle Scholar
• 8 Wang C, Li C, Peng H, Ye Z, Zhang J, Liu X, Lou T. Activation of the Nrf2-ARE pathway attenuates hyperglycemia-mediated injuries in mouse podocytes. Cell Physiol Biochem 2014; 34: 891-902
  CrossrefPubMedGoogle Scholar
• 9 Sit ST, Manser E. Rho GTPases and their role in organizing the actin cytoskeleton. J Cell Sci 2011; 124: 679-683
  CrossrefPubMedGoogle Scholar
• 10 Jiang HS, Zhu LL, Zhang Z, Chen H, Chen Y, Dai YT. Estradiol attenuates the TGF-beta1-induced conversion of primary TAFs into myofibroblasts and inhibits collagen production and myofibroblast contraction by modulating the Smad and Rho/ROCK signaling pathways. Int J Mol Med 2015; 36: 801-807
  PubMedGoogle Scholar
• 11 Li S, Dang Y, Zhou X, Huang B, Huang X, Zhang Z, Kwan YW, Chan SW, Leung GP, Lee SM, Hoi MP. Formononetin promotes angiogenesis through the estrogen receptor alpha-enhanced ROCK pathway. Sci Rep 2015; 5: 16815
  CrossrefPubMedGoogle Scholar
• 12 Cheng L, Xu J, Qian YY, Pan HY, Yang H, Shao MY, Cheng R, Hu T. Interaction between mDia1 and ROCK in Rho-induced migration and adhesion of human dental pulp cells. Int Endod J 2015; DOI: 10.1111/iej.12587.
  PubMedGoogle Scholar
• 13 Kumper S, Mardakheh FK, McCarthy A, Yeo M, Stamp GW, Paul A, Worboys J, Sadok A, Jorgensen C, Guichard S, Marshall CJ. Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis. Elife 2016; DOI: 10.7554/eLife.12203.
  PubMedGoogle Scholar
• 14 Komers R. Rho kinase inhibition in diabetic kidney disease. Br J Clin Pharmacol 2013; 76: 551-559
  PubMedGoogle Scholar
• 15 Hirose A, Tanikawa T, Mori H, Okada Y, Tanaka Y. Advanced glycation end products increase endothelial permeability through the RAGE/Rho signaling pathway. FEBS Lett 2010; 584: 61-66
  CrossrefPubMedGoogle Scholar
• 16 Zhang Y, Peng F, Gao B, Ingram AJ, Krepinsky JC. Mechanical strain-induced RhoA activation requires NADPH oxidase-mediated ROS generation in caveolae. Antioxid Redox Signal 2010; 13: 959-973
  CrossrefPubMedGoogle Scholar
• 17 Kandemir FM, Ozkaraca M, Yildirim BA, Hanedan B, Kirbas A, Kilic K, Aktas E, Benzer F. Rutin attenuates gentamicin-induced renal damage by reducing oxidative stress, inflammation, apoptosis, and autophagy in rats. Ren Fail 2015; 37: 518-525
  CrossrefPubMedGoogle Scholar
• 18 Han Y, Lu JS, Xu Y, Zhang L, Hong BF. Rutin ameliorates renal fibrosis and proteinuria in 5/6-nephrectomized rats by anti-oxidation and inhibiting activation of TGFbeta1-smad signaling. Int J Clin Exp Pathol 2015; 8: 4725-4734
  PubMedGoogle Scholar
• 19 Wagner C, Vargas AP, Roos DH, Morel AF, Farina M, Nogueira CW, Aschner M, Rocha JB. Comparative study of quercetin and its two glycoside derivatives quercitrin and rutin against methylmercury (MeHg)-induced ROS production in rat brain slices. Arch Toxicol 2010; 84: 89-97
  CrossrefPubMedGoogle Scholar
• 20 Sajja RK, Green KN, Cucullo L. Altered Nrf2 signaling mediates hypoglycemia-induced blood-brain barrier endothelial dysfunction in vitro . PLoS One 2015; 10: e0122358
  CrossrefPubMedGoogle Scholar
• 21 Clemmer JS, Xiang L, Lu S, Mittwede PN, Hester RL. Hyperglycemia-mediated oxidative stress increases pulmonary vascular permeability. Microcirculation 2016; DOI: 10.1111/micc.12267.
  PubMedGoogle Scholar
• 22 Ferrari A, Veligodskiy A, Berge U, Lucas MS, Kroschewski R. ROCK-mediated contractility, tight junctions and channels contribute to the conversion of a preapical patch into apical surface during isochoric lumen initiation. J Cell Sci 2008; 121: 3649-3663
  CrossrefPubMedGoogle Scholar
• 23 Gong G, Qin Y, Huang W, Zhou S, Yang X, Li D. Rutin inhibits hydrogen peroxide-induced apoptosis through regulating reactive oxygen species mediated mitochondrial dysfunction pathway in human umbilical vein endothelial cells. Eur J Pharmacol 2010; 628: 27-35
  CrossrefPubMedGoogle Scholar
• 24 Panchal SK, Poudyal H, Arumugam TV, Brown L. Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J Nutr 2011; 141: 1062-1069
  CrossrefPubMedGoogle Scholar
• 25 Ugusman A, Zakaria Z, Chua KH, Nordin NA, Abdullah Mahdy Z. Role of rutin on nitric oxide synthesis in human umbilical vein endothelial cells. ScientificWorldJournal 2014; 2014: 169370
  PubMedGoogle Scholar
• 26 Zuo X, Tian C, Zhao N, Ren W, Meng Y, Jin X, Zhang Y, Ding S, Ying C, Ye X. Tea polyphenols alleviate high fat and high glucose-induced endothelial hyperpermeability by attenuating ROS production via NADPH oxidase pathway. BMC Res Notes 2014; 7: 120
  CrossrefPubMedGoogle Scholar
• 27 Maezawa Y, Takemoto M, Yokote K. Cell biology of diabetic nephropathy: Roles of endothelial cells, tubulointerstitial cells and podocytes. J Diabetes Investig 2015; 6: 3-15
  CrossrefPubMedGoogle Scholar
• 28 Jeansson M, Bjorck K, Tenstad O, Haraldsson B. Adriamycin alters glomerular endothelium to induce proteinuria. J Am Soc Nephrol 2009; 20: 114-122
  CrossrefPubMedGoogle Scholar
• 29 Zhao XY, Wang XF, Li L, Zhang L, Shen DL, Li DH, Jin QS, Zhang JY. Effects of high glucose on human umbilical vein endothelial cell permeability and myosin light chain phosphorylation. Diabetol Metab Syndr 2015; 7: 98
  CrossrefPubMedGoogle Scholar
• 30 Wardle EN. Vascular permeability in diabetics and implications for therapy. Diabetes Res Clin Pract 1994; 23: 135-139
  CrossrefPubMedGoogle Scholar

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