Resveratrol (3,5,4′-trihydroxystilbene), a natural polyphenolic compound found in grapes and red wine, is reported to have beneficial effects on cardiovascular diseases, including renal diseases. These beneficial effects are thought to be due to this compound’s antioxidative properties: resveratrol is known to be a robust scavenger of reactive oxygen species (ROS). In addition to scavenging ROS, resveratrol may have numerous protective effects against age-related disorders, including renal diseases, through the activation of SIRT1. SIRT1, an NAD+-dependent deacetylase, was identified as one of the molecules through which calorie restriction extends the lifespan or delays age-related diseases, and this protein may regulate multiple cellular functions, including apoptosis, mitochondrial biogenesis, inflammation, glucose/lipid metabolism, autophagy, and adaptations to cellular stress, through the deacetylation of target proteins. Previous reports have shown that resveratrol can ameliorate several types of renal injury, such as diabetic nephropathy, drug-induced injury, aldosterone-induced injury, ischemia-reperfusion injury, sepsis-related injury, and unilateral ureteral obstruction, in animal models through its antioxidant effect or SIRT1 activation. Therefore, resveratrol may be a useful supplemental treatment for preventing renal injury. 1. Introduction Chronic kidney disease (CKD), which is characterized by a chronic reduction in the glomerular filtration rate (GFR) and the presence of proteinuria or albuminuria, is recognized as an independent risk factor for both end-stage renal disease (ESRD) and cardiovascular disease, leading to a decrease in quality of life and an increased risk of mortality [1]. Acute kidney injury (AKI) is common in the setting of critical illness and is associated with a high risk of death [2]. In addition, AKI can directly cause ESRD and can increase the risks of the development of incident CKD and the worsening of underlying CKD [3]. Therefore, additional treatment to prevent both chronic and acute kidney injury is necessary. Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic phytoalexin that occurs naturally in many plant parts and products, such as grapes, berries, red wine, and peanut skins [4], and has numerous beneficial health effects. Previous epidemiological studies have revealed an inverse correlation between red wine consumption and the incidence of cardiovascular disease, a phenomenon known as the “French Paradox.” The French population has relatively low rates of cardiovascular disease despite
References
[1]
A. Levin and P. E. Stevens, “Summary of KDIGO guideline: behind the scenes, need for guidance, and a framework for moving forward,” Kidney International, 2013.
[2]
S. Uchino, J. A. Kellum, R. Bellomo et al., “Acute renal failure in critically ill patients: a multinational, multicenter study,” Journal of the American Medical Association, vol. 294, no. 7, pp. 813–818, 2005.
[3]
L. S. Chawla and P. L. Kimmel, “Acute kidney injury and chronic kidney disease: an integrated clinical syndrome,” Kidney International, vol. 82, no. 5, pp. 516–524, 2012.
[4]
A. A. A. Bertelli and D. K. Das, “Grapes, wines, resveratrol, and heart health,” Journal of Cardiovascular Pharmacology, vol. 54, no. 6, pp. 468–476, 2009.
[5]
S. Renaud and M. de Lorgeril, “Wine, alcohol, platelets, and the French paradox for coronary heart disease,” The Lancet, vol. 339, no. 8808, pp. 1523–1526, 1992.
[6]
B. Catalgol, S. Batirel, Y. Taga, and N. K. Ozer, “Resveratrol: French paradox revisited,” Frontiers in pharmacology, vol. 3, article 141, 2012.
[7]
L. Fontana, L. Partridge, and V. D. Longo, “Extending healthy life span-from yeast to humans,” Science, vol. 328, no. 5976, pp. 321–326, 2010.
[8]
H. Y. Cohen, C. Miller, K. J. Bitterman et al., “Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase,” Science, vol. 305, no. 5682, pp. 390–392, 2004.
[9]
L. Guarente, “Sirtuins, aging, and medicine,” The New England Journal of Medicine, vol. 364, no. 23, pp. 2235–2244, 2011.
[10]
M. Kitada, S. Kume, A. Takeda-Watanabe, K. Kanasaki, and D. Koya, “Sirtuins and renal diseases: relationship with aging and diabetic nephropathy,” Clinical Science, vol. 124, no. 3, pp. 153–164, 2013.
[11]
K. T. Howitz, K. J. Bitterman, H. Y. Cohen et al., “Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan,” Nature, vol. 425, no. 6954, pp. 191–196, 2003.
[12]
M. Kitada, S. Kume, K. Kanasaki, et al., “Sirtuins as possible drug targets in type 2 diabetes,” Current Drug Targets, vol. 14, no. 6, pp. 622–636, 2013.
[13]
W. Dr？ge, “Free radicals in the physiological control of cell function,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002.
[14]
W. Droge, “Oxidative stress and aging,” in Hypoxia, C. R. Roach, D. P. Wagner, and H. P. Hackett, Eds., vol. 543 of Advances in Experimental Medicine and Biology, pp. 191–200, 2003.
[15]
J. H. Holthoff, K. A. Woodling, D. R. Doerge, S. T. Burns, J. A. Hinson, and P. R. Mayeux, “Resveratrol, a dietary polyphenolic phytoalexin, is a functional scavenger of peroxynitrite,” Biochemical Pharmacology, vol. 80, no. 8, pp. 1260–1265, 2010.
[16]
S. S. Leonard, C. Xia, B.-H. Jiang et al., “Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses,” Biochemical and Biophysical Research Communications, vol. 309, no. 4, pp. 1017–1026, 2003.
[17]
S. Pervaiz and A. L. Holme, “Resveratrol: its biologic targets and functional activity,” Antioxidants and Redox Signaling, vol. 11, no. 11, pp. 2851–2897, 2009.
[18]
E. L. Robb, L. Winkelmolen, N. Visanji, J. Brotchie, and J. A. Stuart, “Dietary resveratrol administration increases MnSOD expression and activity in mouse brain,” Biochemical and Biophysical Research Communications, vol. 372, no. 1, pp. 254–259, 2008.
[19]
M. Mokni, S. Elkahoui, F. Limam, M. Amri, and E. Aouani, “Effect of resveratrol on antioxidant enzyme activities in the brain of healthy rat,” Neurochemical Research, vol. 32, no. 6, pp. 981–987, 2007.
[20]
M. Kitada, S. Kume, N. Imaizumi, and D. Koya, “Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1- independent pathway,” Diabetes, vol. 60, no. 2, pp. 634–643, 2011.
[21]
R. J. Colman, R. M. Anderson, S. C. Johnson et al., “Caloric restriction delays disease onset and mortality in rhesus monkeys,” Science, vol. 325, no. 5937, pp. 201–204, 2009.
[22]
L. Fontana, T. E. Meyer, S. Klein, and J. O. Holloszy, “Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 17, pp. 6659–6663, 2004.
[23]
T. E. Meyer, S. J. Kovács, A. A. Ehsani, S. Klein, J. O. Holloszy, and L. Fontana, “Long-term caloric restriction ameliorates the decline in diastolic function in humans,” Journal of the American College of Cardiology, vol. 47, no. 2, pp. 398–402, 2006.
[24]
S.-I. Imai, C. M. Armstrong, M. Kaeberlein, and L. Guarente, “Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase,” Nature, vol. 403, no. 6771, pp. 795–800, 2000.
[25]
L. Bordone, D. Cohen, A. Robinson et al., “SIRT1 transgenic mice show phenotypes resembling calorie restriction,” Aging Cell, vol. 6, no. 6, pp. 759–767, 2007.
[26]
G. Bellot, R. Garcia-Medina, P. Gounon et al., “Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains,” Molecular and Cellular Biology, vol. 29, no. 10, pp. 2570–2581, 2009.
[27]
G. R. Steinberg and B. E. Kemp, “AMPK in health and disease,” Physiological Reviews, vol. 89, no. 3, pp. 1025–1078, 2009.
[28]
S.-J. Park, F. Ahmad, A. Philp et al., “Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases,” Cell, vol. 148, no. 3, pp. 421–433, 2012.
[29]
N. L. Price, A. P. Gomes, A. J. Y. Ling et al., “SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function,” Cell Metabolism, vol. 15, no. 5, pp. 675–690, 2012.
[30]
B. P. Hubbard, A. P. Gomes, H. Dai, et al., “Evidence for a common mechanism of SIRT1 regulation by allosteric activators,” Science, vol. 339, no. 6124, pp. 1216–1219, 2013.
[31]
M. Kitada, Z. Zhang, A. Mima, and G. L. King, “Molecular mechanisms of diabetic vascular complications,” Journal of Diabetes Investigation, vol. 1, no. 3, pp. 77–89, 2010.
[32]
S. Sharma, M. Anjaneyulu, S. K. Kulkarni, and K. Chopra, “Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats,” Pharmacology, vol. 76, no. 2, pp. 69–75, 2006.
[33]
P. Palsamy and S. Subramanian, “Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling,” Biochimica et Biophysica Acta, vol. 1812, no. 7, pp. 719–731, 2011.
[34]
M. Y. Kim, J. H. Lim, H. H. Youn, et al., “Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice,” Diabetologia, vol. 56, no. 1, pp. 204–217, 2013.
[35]
L. Zhang, S. Pang, B. Deng et al., “High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol,” International Journal of Biochemistry and Cell Biology, vol. 44, no. 4, pp. 629–638, 2012.
[36]
D.-F. Ding, N. You, X.-M. Wu et al., “Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK,” American Journal of Nephrology, vol. 31, no. 4, pp. 363–374, 2010.
[37]
M.-J. Lee, D. Feliers, K. Sataranatarajan et al., “Resveratrol ameliorates high glucose-induced protein synthesis in glomerular epithelial cells,” Cellular Signalling, vol. 22, no. 1, pp. 65–70, 2010.
[38]
K. Tikoo, K. Singh, D. Kabra, V. Sharma, and A. Gaikwad, “Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy,” Free Radical Research, vol. 42, no. 4, pp. 397–404, 2008.
[39]
L. Wu, Y. Zhang, X. Ma, N. Zhang, and G. Qin, “The effect of resveratrol on FoxO1 expression in kidneys of diabetic nephropathy rats,” Molecular Biology Reports, vol. 39, no. 9, pp. 9085–9093, 2012.
[40]
Y. Xu, L. Nie, Y.-G. Yin et al., “Resveratrol protects against hyperglycemia-induced oxidative damage to mitochondria by activating SIRT1 in rat mesangial cells,” Toxicology and Applied Pharmacology, vol. 259, no. 3, pp. 395–401, 2012.
[41]
K.-H. Chen, C.-C. Hung, H.-H. Hsu, Y.-H. Jing, C.-W. Yang, and J.-K. Chen, “Resveratrol ameliorates early diabetic nephropathy associated with suppression of augmented TGF-β/smad and ERK1/2 signaling in streptozotocin-induced diabetic rats,” Chemico-Biological Interactions, vol. 190, no. 1, pp. 45–53, 2011.
[42]
R. P. Miller, R. K. Tadagavadi, G. Ramesh, and W. B. Reeves, “Mechanisms of cisplatin nephrotoxicity,” Toxins, vol. 2, no. 11, pp. 2490–2518, 2010.
[43]
C. L. Do Amaral, H. D. C. Francescato, T. M. Coimbra et al., “Resveratrol attenuates cisplatin-induced nephrotoxicity in rats,” Archives of Toxicology, vol. 82, no. 6, pp. 363–370, 2008.
[44]
D. H. Kim, Y. J. Jung, J. E. Lee et al., “Sirt1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53,” American Journal of Physiology: Renal Physiology, vol. 301, no. 2, pp. F427–F435, 2011.
[45]
T. de Jesus Soares, R. A. Volpini, H. D. C. Francescato, R. S. Costa, C. G. A. da Silva, and T. M. Coimbra, “Effects of resveratrol on glycerol-induced renal injury,” Life Sciences, vol. 81, no. 8, pp. 647–656, 2007.
[46]
V. Chander and K. Chopra, “Protective effect of resveratrol, a polyphenolic phytoalexin on glycerol-induced acute renal failure in rat kidney,” Renal Failure, vol. 28, no. 2, pp. 161–169, 2006.
[47]
A. I. Morales, J. M. Buitrago, J. M. Santiago, M. Fernández-Tagarro, J. M. López-Novoa, and F. Pérez-Barriocanal, “Protective effect of trans-Resveratrol on gentamicin-induced nephrotoxicity,” Antioxidants and Redox Signaling, vol. 4, no. 6, pp. 893–898, 2002.
[48]
C. Silan, ？. Uzun, N. ü. ？omuno？lu, S. Gok？en, S. Bedirhan, and M. Cengiz, “Gentamicin-induced nephrotoxicity in rats ameliorated and healing effects of resveratrol,” Biological and Pharmaceutical Bulletin, vol. 30, no. 1, pp. 79–83, 2007.
[49]
V. Chander, N. Tirkey, and K. Chopra, “Resveratrol, a polyphenolic phytoalexin protects against cyclosporine-induced nephrotoxicity through nitric oxide dependent mechanism,” Toxicology, vol. 210, no. 1, pp. 55–64, 2005.
[50]
Y. Yuan, S. Huang, W. Wang, et al., “Activation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury,” Kidney International, vol. 82, no. 7, pp. 771–789, 2012.
[51]
S. C. Weight, P. R. F. Bell, and M. L. Nicholson, “Renal ischaemia-reperfusion injury,” British Journal of Surgery, vol. 83, no. 2, pp. 162–170, 1996.
[52]
L. Giovannini, M. Migliori, B. M. Longoni et al., “Resveratrol, a polyphenol found in wine, reduces ischemia reperfusion injury in rat kidneys,” Journal of Cardiovascular Pharmacology, vol. 37, no. 3, pp. 262–270, 2001.
[53]
V. Chander and K. Chopra, “Protective effect of nitric oxide pathway in resveratrol renal ischemia-reperfusion injury in rats,” Archives of Medical Research, vol. 37, no. 1, pp. 19–26, 2006.
[54]
Q. Xu, X. Hao, Q. Yang, and L. Si, “Resveratrol prevents hyperglycemia-induced endothelial dysfunction via activation of adenosine monophosphate-activated protein kinase,” Biochemical and Biophysical Research Communications, vol. 388, no. 2, pp. 389–394, 2009.
[55]
G. Arunachalam, H. Yao, I. K. Sundar, S. Caito, and I. Rahman, “SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: role of resveratrol,” Biochemical and Biophysical Research Communications, vol. 393, no. 1, pp. 66–72, 2010.
[56]
N. Xia, S. Strand, F. Schlufter, et al., “Role of SIRT1 and FOXO factors in eNOS transcriptional activation by resveratrol,” Nitric Oxide, vol. 32, pp. 29–35, 2013.
[57]
S. Heemskerk, R. Masereeuw, F. G. M. Russel, and P. Pickkers, “Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury,” Nature Reviews Nephrology, vol. 5, no. 11, pp. 629–640, 2009.
[58]
N. Mayeur, V. Minville, A. Jaafar et al., “Morphologic and functional renal impact of acute kidney injury after prolonged hemorrhagic shock in mice,” Critical Care Medicine, vol. 39, no. 9, pp. 2131–2138, 2011.
[59]
L. Wu, N. Gokden, and P. R. Mayeux, “Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury,” Journal of the American Society of Nephrology, vol. 18, no. 6, pp. 1807–1815, 2007.
[60]
L. Wu, M. M. Tiwari, K. J. Messer et al., “Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice,” American Journal of Physiology: Renal Physiology, vol. 292, no. 1, pp. F261–F268, 2007.
[61]
J. H. Holthoff, Z. Wang, K. A. Seely, N. Gokden, and P. R. Mayeux, “Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury,” Kidney International, vol. 81, no. 4, pp. 370–378, 2012.
[62]
R. L. Chevalier, M. S. Forbes, and B. A. Thornhill, “Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy,” Kidney International, vol. 75, no. 11, pp. 1145–1152, 2009.
[63]
J. Li, X. Qu, S. D. Ricardo, J. F. Bertram, and D. J. Nikolic-Paterson, “Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3,” American Journal of Pathology, vol. 177, no. 3, pp. 1065–1071, 2010.
[64]
S. Kume, T. Uzu, K. Horiike et al., “Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1043–1055, 2010.
[65]
K. Inoki, H. Mori, J. Wang et al., “mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2181–2196, 2011.
[66]
M. G？del, B. Hartleben, N. Herbach et al., “Role of mTOR in podocyte function and diabetic nephropathy in humans and mice,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2197–2209, 2011.
[67]
M. Sakaguchi, M. Isono, K. Isshiki, T. Sugimoto, D. Koya, and A. Kashiwagi, “Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice,” Biochemical and Biophysical Research Communications, vol. 340, no. 1, pp. 296–301, 2006.
[68]
W. Lieberthal and J. S. Levine, “Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications,” American Journal of Physiology: Renal Physiology, vol. 303, no. 2, pp. 180–191, 2012.
[69]
M. Liu, S. A. Wilk, A. Wang et al., “Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR,” Journal of Biological Chemistry, vol. 285, no. 47, pp. 36387–36394, 2010.
