Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats
© Yang et al.; licensee BioMed Central Ltd. 2014
Received: 6 December 2013
Accepted: 20 May 2014
Published: 27 May 2014
The metabolic syndrome is associated with an increased risk of development and progression of chronic kidney disease. Renal inflammation is well known to play an important role in the initiation and progression of tubulointerstitial injury of the kidneys. Ginger, one of the most commonly used spices and medicinal plants, has been demonstrated to improve diet-induced metabolic abnormalities. However, the efficacy of ginger on the metabolic syndrome-associated kidney injury remains unknown. This study aimed to investigate the impact of ginger on fructose consumption-induced adverse effects in the kidneys.
The fructose control rats were treated with 10% fructose in drinking water over 5 weeks. The fructose consumption in ginger-treated rats was adjusted to match that of fructose control group. The ethanolic extract of ginger was co-administered (once daily by oral gavage). The indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by Real-Time PCR.
In addition to improve hyperinsulinemia and hypertriglyceridemia, supplement with ginger extract (50 mg/kg) attenuated liquid fructose-induced kidney injury as characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex of the kidneys in rats. Furthermore, ginger also diminished excessive renal interstitial collagen deposit. By Real-Time PCR, renal gene expression profiles revealed that ginger suppressed fructose-stimulated monocyte chemoattractant protein-1 and its receptor chemokine (C-C motif) receptor-2. In accord, overexpression of two important macrophage accumulation markers CD68 and F4/80 was downregulated. Moreover, overexpressed tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta1 and plasminogen activator inhibitor (PAI)-1 were downregulated. Ginger treatment also restored the downregulated ratio of urokinase-type plasminogen activator to PAI-1.
The present results suggest that ginger supplement diminishes fructose-induced kidney injury through suppression of renal overexpression of macrophage-associated proinflammatory cytokines in rats. Our findings provide evidence supporting the protective effect of ginger on the metabolic syndrome-associated kidney injury.
KeywordsZingiber officinale Roscoe Renoprotection Anti-inflammation Metabolic abnormalities
The metabolic syndrome is a well-established risk factor for diabetes, cardiovascular disease and mortality. Recently, studies have suggested that the metabolic syndrome may also contribute to the development of chronic kidney disease. Data from the Third National Health and Nutrition Examination Survey has shown an independent association between the metabolic syndrome and chronic kidney disease . This connection has been further corroborated by the finding that the metabolic syndrome increases the risk of developing new-onset chronic kidney disease . Indeed, renal injury is often seen in various animal models of the metabolic syndrome, such as Zucker diabetic fatty rats [3, 4] and db/db mice .
The Western-style diet, characterized by an overavailability of food, with high intakes of high-fat foods, high-sugar desserts and drinks, as well as high intakes of red meat, refined grains, and high-fat dairy products, affects multiple metabolic functions and has been associated with a higher incidence of the metabolic syndrome. It has been suggested that the Western-style diet is a major risk factor for impaired kidney function and chronic kidney disease . Notably, fructose has now become a major constituent of our modern diet. Fructose consumption has steadily increased over the past 30 years in parallel to the growth of the obesity/metabolic syndrome epidemic, and fructose and high-fructose corn syrup are ingredients in many commercially produced food products . It has been hypothesized that fructose consumption in our diet may be among the factors that contribute to the epidemic of the metabolic syndrome and, consequently, to the epidemic of chronic renal disease [1, 7–11]. This hypothesis is supported by the preliminary evidence demonstrating that high fructose consumption induces kidney damages in both rats [12–14] and mice .
Ginger (Zingiber officinale Roscoe, Zingiberacae) is one of the most commonly used spices and medicinal plants around the world. It has been demonstrated that ginger has pleiotropic pharmacological activities, such as gastrointestinal, analgesic, anti-inflammatory, antioxidant and cardiovascular activities [16, 17]. The renoprotective effects of ginger have also been reported in the animal models of ischemia/reperfusion- [18, 19], alcohol- [20, 21], streptozotocin-  and carbon tetrachloride-  induced renal injuries. However, the efficacy of ginger on the metabolic syndrome-associated kidney damages remains unknown. We have recently demonstrated that ginger supplement improves fructose consumption-induced fatty liver  and adipose tissue insulin resistance  in rats. In the present study, we examined the impact of ginger on chronic fructose consumption-induced kidney injury in rats. Furthermore, the underlying mechanisms were also investigated.
Preparation and identification of the ethanolic extract of ginger
Ginger rhizomes were collected from the suburban area of Hanoi, Vietnam, and identified botanically by Professor Johji Yamahara, who is an expert in taxonomy. A voucher specimen was deposited in Pharmafood Institute, Kyoto, Japan (Voucher specimen No: PS0088). The extract used in the present study was prepared using an ethanolic method described previously . Briefly, 5 kg of sliced dry ginger rhizomes including the skins were immersed in 5 L of 95% ethanol with intermittent shaking for 24 h, and then refluxed for 3 h by heating. The filtrate was evaporated below 45°C under reduced pressure. The residue (yield: 9.6%) was designated as an alcoholic extract. The extract was quantified by a HPLC method described previously  to contain two representative components: 6-gingerol and 6-shogaol at 4.4% and 1.1%, respectively.
Animals, diet and experimental protocol
All animal procedures were in accordance with the ‘Principles of laboratory animal care’ (http://grants1.nih.gov/grants/olaw/references/phspol.htm) and were approved by the Animal Ethics Committee of Chongqing Medical University, China.
Male Sprague–Dawley rats aged 7–9 weeks (210–230 g) and standard laboratory chow were supplied by the Laboratory Animal Center, Chongqing Medical University, China. Rats were housed in a temperature controlled facility (21 ± 1°C, 55 ± 5% relative humidity) with a 12-h light/dark cycle. Animals were allowed free access to water and standard chow for at least 1 week prior to starting the experiments.
Research has shown that sugar-sweetened nonalcoholic beverages, such as soft drinks, appear as the major source of fructose for all classes of age considered, except for children younger than 6 years and adults older than 50 years . Therefore, fructose in drinking water was used in the present study, in accordance to this rationale and the previous research protocol [24, 25, 28, 29].
Dosage selection is of exceptional importance for pharmacological intervention. Excessively high dosages in animals may result in non-specific (“artificial”) effects, which may be dissociated with those in humans. A 35-day toxicity study in rats has demonstrated that the dried ginger powder at the dosages of 500, 1000 and 2000 mg/kg (equivalent to 48–192 mg/kg ethanolic extract used in the present study) was not associated with any mortalities and abnormalities in general conditions, behavior, growth, food and water consumption, hematological and blood biochemical parameters . Previous studies have reported that treatment with dried ginger powder at a dosage of 200  or 500  mg/kg (equivalent to 19.2 or 48 mg/kg ethanolic extract used in the present study) alleviated streptozotocin-induced the metabolic syndrome-associated or renal dysfunctions in rats. In humans, 3–9 g dried ginger (equivalent to 288–864 mg ethanolic extract used in the present study) is the officially accepted dosages (Version 1, 2010 Chinese Pharmacopoeia). Based on the above information, the dosages of 20 and 50 mg/kg ethanolic extract were selected for the present study.
Twenty-four rats were divided into 4 groups (n = 6 per group): (1) water control, free access to water; (2) fructose control, free access to 10% fructose solution (w/v, preparation every day); (3) fructose + ginger 20 mg/kg and (4) fructose + ginger 50 mg/kg. There was no difference in body weight between the groups before treatments commenced. Animals in ginger-treated groups were administered ginger extract at 20 and 50 mg/kg (suspended in 5% Gum Arabic solution, gavage once daily) for 5 weeks, respectively. The rats in the corresponding water- and fructose-control groups received vehicle (5% Gum Arabic) alone. All rats had free access to the standard chow. To avoid stress and maintain accurate monitoring of fructose intake, only 2 rats were housed in a cage at any given time. The consumed chow and fructose solution were measured per 2 rats daily and the intake of fructose was calculated. Initial experiments showed that when compared to the vehicle alone, ginger treatment significantly increased the intake of the 10% fructose water when the rats were given free access. In order to exclude the influence resulting from differences in fructose intake, fructose consumption in the groups treated with the ginger extracts were adjusted by regulating the concentration of fructose solution daily to match that of the fructose control group on the previous day.
At the end of week 4, the rats were fasted overnight before blood samples were collected by retroorbital venous puncture under ether anesthesia at 9:00–12:00 am for determination of plasma concentrations of total cholesterol (kit from Kexin Institute of Biotechnology, Shanghai, China), triglyceride (Triglyceride-E kit, Wako, Osaka, Japan), glucose (kit from Kexin Institute of Biotechnology, Shanghai, China) and insulin (kit from Morinaga Biochemical Industries, Tokyo, Japan). At the end of week 5, the rats were weighed and killed by prompt dislocation of the neck vertebra. Kidneys and epididymal fat tissues were collected and weighed. The ratio of kidney weight to body weight was calculated. Segments of kidney were flash frozen in liquid nitrogen and stored at -80°C for subsequent determination of lipid contents and gene expression.
Histological examination of kidney
All slides were examined by two different researchers in a blinded manner. Morphometric quantification was assessed by microscopy (IX-81, Olympus Corporation, Tokyo, Japan) using a NIH ImageJ (version 1.43) analyzing system.
A portion of kidney was fixed with 10% formalin and embedded in paraffin. Three-micron thick sections were cut and stained with hematoxylin and eosin. The sections were imaged and cross-sectional areas were estimated in glomeruli that were cut transversely. The outer borders of the glomeruli were traced at 200 × magnification, and glomerular tuft area was measured. Fifty glomeruli per kidney were counted, and the mean values of these estimates were used in analyses. To further investigate the damage, an additional section (two-micron thickness) fixed in a 4% paraformaldehyde solution was stained with periodic acid-Schiff (PAS) and examined as previously described  using light microscopy and blinded assessors. Tubular size was determined by outlining each tubular profile. 200 tubules in each kidney section were examined. Tubular injury (by counting the number of tubules that exhibited cast formation, slough and dilation of tubular epithelial cells) was evaluated.
To determine the degree of collagen fiber accumulation, a kidney section (two-micron thickness) was stained with Masson’s trichrome. Forty fields in different sections were randomly selected, and Masson’s trichrome-stained area (blue) and total tissue area were determined. Their ratio was calculated as interstitial collagen deposit (fibrosis).
To observe lipid accumulation, six-micron frozen kidney sections were stained with Oil Red O.
Determination of triglyceride and total cholesterol contents in kidney
Triglyceride and total cholesterol contents in kidney were determined as described previously [24, 28]. Briefly, 100 mg of tissue was homogenized and extracted with 2 ml of isopropanol. After centrifugation (1000 × g, 10 min at 4°C), the triglyceride and total cholesterol contents in supernatants were determined enzymatically (Wako, Osaka, Japan).
Primer sequences for Real Time PCR assays
All results are expressed as means ± SEM. Data were analyzed by ANOVA using the StatView software (Version 5.0.1, SAS Institute Inc. USA), and followed by The Student-Newman-Keuls test to locate the differences between groups. P < 0.05 was considered to be statistically significant.
General characteristics of the effects of ginger extract in fructose-fed rats
General parameters (n=6)
Fructose intake (g/2 rats/5 w)
Chow intake (g/2 rats/5 w)
Body weight (g)
Epididymal fat weight (g)
Plasma glucose (mmol/L)
Plasma insulin (pmol/L)
Plasma TG (mmol/L)
Plasma TC (mmol/L)
Plasma BUN (mmol/L)
Plasma creatinine (μmol/L)
Effects on kidney-related variables in rats
Renal gene expression profiles in rats
Ginger has been demonstrated to protect rats from ischemia/reperfusion- [18, 19], alcohol- [20, 21], streptozotocin-  and carbon tetrachloride-  induced renal injuries. Recently, we have demonstrated that ginger supplement improves fructose consumption-induced fatty liver  and adipose tissue insulin resistance  in rats. The present study investigated the effects of ginger on chronic fructose consumption-associated kidney injury. Consistent with the previous findings , the present results demonstrate that five-week fructose consumption induced kidney remodeling as characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex and outer stripe of the medullas, and excessive interstitial collagen deposit in rats. However, these pathological changes were accompanied by minimal alteration in glomerular structure and concentrations of BUN and plasma creatinine. It is possible that the mild initial histological changes do not induce pronounced alterations in renal functionality. Supplementing with a ginger extract (50 mg/kg) attenuated the proximal tubular damage and interstitial fibrosis in the kidneys and these effects were accompanied by improvements in hyperinsulinemia and hypertriglyceridemia. Therefore, these results present evidence suggesting that ginger possesses protective effect against the initial stages of the metabolic syndrome-associated kidney injury.
Renal inflammation is known to play an important role in the initiation and progression of tubulointerstitial injury in the kidneys [32, 33]. Fructose has been demonstrated to induce production of macrophage-associated MCP-1 in human kidney proximal tubular cells . Fructose consumption leads to cortical tubular damage with inflammatory infiltrates . MCP-1 promotes monocyte and macrophage migration and activation, and upregulates expression of adhesion molecules and other proinflammatory cytokines. Studies indicate that the local expression of MCP-1 at sites of renal injury promotes macrophage adhesion and chemotaxis through ligation of CCR-2 . In patients, tubular MCP-1 is elevated in progressive renal diseases  and albuminuria is associated with MCP-1 and macrophage infiltration . The infiltrated macrophages produce numerous proinflammatory cytokines, such as TNF-α , which has been shown to mediate inflammation in several models of renal injury, including tubulointerstitial injury . It has been reported that gingerols, -shogaol and 1-dehydro--gingerdione inhibit lipopolysaccharide-stimulated release and gene expression of proinflammatory cytokines including MCP-1 and IL-6 in RAW 264.7 macrophages and cultured primary rat astrocytes [40–43]. In addition, another component of ginger, known as zingerone, has also been shown to suppress the inflammatory action of macrophages and release of MCP-1 from adipocytes, thereby blunting the inflammatory response of adipose tissue in obesity . These findings have been corroborated by a study we have recently conducted in rats demonstrating the modulatory effects of ginger on adipose expression of macrophage-related proinflammatory cytokines thereby ameliorating fructose-induced adipose tissue insulin resistance . The present study found that the ginger extract containing -gingerol and -shogaol was able to suppress fructose-induced overexpression of MCP-1, CCR-2, CD68 and F4/80 (two important macrophage markers [45, 46]), TNF-α and IL-6 in the kidneys. These findings are consistent with the attenuation of proximal tubular injury. Thus, the renoprotective effect of ginger supplement is associated with suppression of renal overexpression of macrophage-associated proinflammatory cytokines.
Proinflammatory cytokines are associated with renal fibrosis. It has been demonstrated that blockading MCP-1 and its receptor CCR-2 pathway reduces renal fibrosis . The activated macrophages also produce other proinflammatory cytokines, such as IL-6, TGF-β1 and PAI-1 . IL-6 was shown to enhance TGF-β1 signaling via modulation of TGF-β1 receptor trafficking, an effect that may enhance renal fibrosis . TGF-β1 may activate the plasmin system by stimulating gene expression of PAI-1, the principal inhibitor of plasminogen activation . PAI-1 has a number of important roles in pathophysiological processes, such as inhibition of fibrinolysis, regulation of extracellular matrix turnover and activation of proenzymes and latent growth factors that promote tissue fibrosis and sclerosis . In progressive renal diseases, PAI-1 has been identified as a critical mediator of glomerulosclerosis and interstitial fibrosis [50, 51]. The altered uPA to PAI-1 ratio reflects a change from a profibrinolytic to an antifibrinolytic state . The shift toward the uPA-enriched profibrinolytic state favors renal collagen degradation. Given its pathophysiological role, studies into TGF-β1 have found that -gingerol inhibits its stimulation of myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts  and of proteoglycan core protein synthesis in human vascular smooth muscle cells . In the present study, fructose-induced upregulation of MCP-1, CCR-2, IL-6, TGF-β1 and PAI-1 gene expression in kidney was suppressed by ginger supplement (50 mg/kg). The ratio of uPA to PAI-1 was also restored. Thus, ginger-elicited diminishment of renal interstitial fibrosis is also associated with suppression of renal overexpression of proinflammatory cytokines, thereby improving profibrinolytic state.
Lipid accumulation in nonadipose tissues has been increasingly recognized to contribute to organ injury through a process termed lipotoxicity. There is substantial evidence that excess renal lipids can cause injury in animal models of metabolic disease (obesity, metabolic syndrome and diabetes mellitus), chronic kidney disease, acute renal injury of several etiologies, as well as aging . Lipotoxic cellular dysfunction and injury occur through several mechanisms such as release of proinflammatory and profibrotic factors . Fructose consumption may induce excessive lipid accumulation in liver . We have recently demonstrated that treatment with the ethanolic extract of ginger attenuates fructose-induced fatty liver in rats . In the present study, however, five-week fructose feeding did not alter renal accumulation of triglyceride and total cholesterol in rats. Ginger treatment (20 and 50 mg/kg) also did not affect renal lipid contents in fructose-fed rats. Thus, it is unlikely that ginger treatment ameliorates fructose-induced renal injury in rats via modification of renal lipid metabolism.
While there are numerous constituents in ginger, the two prominent components -gingerol and -shogaol have been implicated in the majority of pharmacological activities associated with ginger . At this point, further investigation is needed to broaden our collective knowledge regarding the details surrounding the therapeutic actions of ginger. Specifically, whether -gingerol, -shogaol, or a combination thereof is responsible for the diminishment of fructose-induced renal injury, their specific function on macrophages, and the manner in which they suppress proinflammatory cytokines.
Our present results demonstrate that supplement with ginger extract at 50 mg/kg attenuates chronic fructose consumption-induced kidney injury in rats by suppressing renal overexpression of proinflammatory cytokines. Our findings provide evidence supporting the benefit of ginger supplement for the metabolic syndrome-associated kidney injury.
Blood urea nitrogen
Chemokine (C-C motif) receptor
Monocyte chemoattractant protein
Plasminogen activator inhibitor
Transforming growth factor
Tumor necrosis factor
Urokinase-type plasminogen activator.
We thank Mr. Alan Yeung for his excellent assistance in the preparation of this manuscript. This work was financially supported by National Natural Science Foundation of China (Grant 81374033), China, and R&D Agency for Curative Natural Products (a Japanese government-registered non-profit organization), Kyoto, Japan.
- Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J: The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med. 2004, 140: 167-174. 10.7326/0003-4819-140-3-200402030-00007.View ArticlePubMedGoogle Scholar
- Kurella M, Lo JC, Chertow GM: Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol. 2005, 16: 2134-2140. 10.1681/ASN.2005010106.View ArticlePubMedGoogle Scholar
- Li Y, Qi Y, Kim MS, Xu KZY, Huang THW, Rong X, Murray M, Yamahara J: Increased renal collagen cross-linking and lipid accumulation in nephropathy of Zucker diabetic fatty rats. Diabetes-metab Res Rev. 2008, 24: 498-506. 10.1002/dmrr.874.View ArticlePubMedGoogle Scholar
- He L, Qi Y, Rong X, Jiang J, Yang Q, Yamahara J, Murray M, Li Y: The Ayurvedic medicine Salacia oblonga attenuates diabetic renal fibrosis in rats: suppression of angiotensin II/AT1 signaling. Evid-Based Complement Alternat Med. 2011, 2011: 807451-PubMedPubMed CentralGoogle Scholar
- Ziyadeh FN, Hoffman BB, Han DC, La Cruz MC I-D, Hong SW, Isono M, Chen S, McGowan TA, Sharma K: Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal anti-transforming growth factor-antibody in db/db diabetic mice. Proc Natl Acad Sci USA. 2000, 97: 8015-8020. 10.1073/pnas.120055097.View ArticlePubMedPubMed CentralGoogle Scholar
- Odermatt A: The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. Am J Physiol Renal Physiol. 2011, 301: F919-F931. 10.1152/ajprenal.00068.2011.View ArticlePubMedGoogle Scholar
- Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ: Fructose, weight gain, and the insulin resistance syndrome. Am J Clin Nutr. 2002, 76: 911-922.PubMedGoogle Scholar
- Jacobson MF: High-fructose corn syrup and the obesity epidemic. Am J Clin Nutr. 2004, 80: 1081-1082.PubMedGoogle Scholar
- Jürgens H, Haass W, Castaneda TR, Schürmann A, Koebnick C, Dombrowski F, Otto B, Nawrocki AR, Scherer PE, Spranger J, Ristow M, Joost HJ, Havel PJ, Tschöp MH: Consuming fructose‒sweetened beverages increases body adiposity in mice. Obes Res. 2005, 13: 1146-1156. 10.1038/oby.2005.136.View ArticlePubMedGoogle Scholar
- Nakagawa T, Tuttle KR, Short RA, Johnson RJ: Hypothesis: fructoseinduced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol. 2005, 1: 80-86.View ArticlePubMedGoogle Scholar
- Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Johnson RJ: A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006, 290: F625-F631.View ArticlePubMedGoogle Scholar
- Kizhner T, Werman MJ: Long-term fructose intake: biochemical consequences and altered renal histology in the male rat. Metabolism. 2002, 51: 1538-1547. 10.1053/meta.2002.36306.View ArticlePubMedGoogle Scholar
- Nakayama T, Kosugi T, Gersch M, Connor T, Sanchez-Lozada LG, Lanaspa MA, Roncal C, Perez-Pozo SE, Johnson RJ, Nakagawa T: Dietary fructose causes tubulointerstitial injury in the normal rat kidney. Am J Physiol Renal Physiol. 2010, 2010 (298): F712-F720.View ArticleGoogle Scholar
- Oudot C, Lajoix AD, Jover B, Rugale C: Dietary sodium restriction prevents kidney damage in high fructose-fed rats. Kidney Int. 2013, 83: 674-683. 10.1038/ki.2012.478.View ArticlePubMedGoogle Scholar
- Aoyama M, Isshiki K, Kume S, Chin-Kanasaki M, Araki H, Araki SI, Koya D, Haneda M, Kashiwagi A, Maegawa H, Uzu T: Fructose induces tubulointerstitial injury in the kidney of mice. Biochem Biophys Res Commun. 2012, 419: 244-249. 10.1016/j.bbrc.2012.02.001.View ArticlePubMedGoogle Scholar
- Ali BH, Blunden G, Tanira MO, Nemmar A: Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol. 2008, 46: 409-420. 10.1016/j.fct.2007.09.085.View ArticlePubMedGoogle Scholar
- Nicoll R, Henein MY: Ginger (Zingiber officinale Roscoe): A hot remedy for cardiovascular disease?. Int J Cardiol. 2009, 131: 408-409. 10.1016/j.ijcard.2007.07.107.View ArticlePubMedGoogle Scholar
- Uz E, Karatas OF, Mete E, Bayrak R, Bayrak O, Atmaca AF, Atis O, Yildirim ME, Akcay A: The effect of dietary ginger (Zingiber officinals Rosc) on renal ischemia/reperfusion injury in rat kidneys. Ren Fail. 2009, 31: 251-260. 10.1080/08860220902779921.View ArticlePubMedGoogle Scholar
- Maghsoudi S, Gol A, Dabiri S, Javadi A: Preventive effect of ginger (Zingiber officinale) pretreatment on renal ischemia-reperfusion in rats. Eur Surg Res. 2011, 46: 45-51. 10.1159/000321704.View ArticlePubMedGoogle Scholar
- Shanmugam KR, Ramakrishna CH, Mallikarjuna K, Reddy KS: Protective effect of ginger against alcohol-induced renal damage and antioxidant enzymes in male albino rats. Indian J Exp Biol. 2010, 48: 143-149.PubMedGoogle Scholar
- Ramudu SK, Korivi M, Kesireddy N, Chen CY, Kuo CH, Kesireddy S: Ginger feeding protects against renal oxidative damage caused by alcohol consumption in rats. J Ren Nutr. 2011, 21: 263-270. 10.1053/j.jrn.2010.03.003.View ArticlePubMedGoogle Scholar
- Ramudu SK, Korivi M, Kesireddy N, Lee LC, Cheng IS, Kuo CH, Kesireddy SR: Nephro-protective effects of a ginger extract on cytosolic and mitochondrial enzymes against streptozotocin (STZ)-induced diabetic complications in rats. Chin J Physiol. 2011, 54: 79-86. 10.4077/CJP.2011.AMM006.View ArticlePubMedGoogle Scholar
- Hamed MA, Ali SA, El-Rigal NS: Therapeutic potential of ginger against renal injury induced by carbon tetrachloride in rats. ScientificWorldJournal. 2012, 2012: 840421-View ArticlePubMedPubMed CentralGoogle Scholar
- Gao H, Guan T, Li C, Zuo G, Yamahara J, Wang J, Li Y: Treatment with ginger ameliorates fructose-induced fatty liver and hypertriglyceridemia in rats: modulation of the hepatic carbohydrate response element binding protein-mediated pathway. Evid-Based Complement Alternat Med. 2012, 2012: 570948-PubMedPubMed CentralGoogle Scholar
- Wang J, Gao H, Ke D, Zuo G, Yang Y, Yamahara J, Li Y: Improvement of liquid fructose-induced adipose tissue insulin resistance by ginger treatment in rats is associated with suppression of adipose macrophage-related pro-inflammatory cytokines. Evid-Based Complement Alternat Med. 2013, 2013: 590376-PubMedPubMed CentralGoogle Scholar
- Rong X, Peng G, Suzuki T, Yang Q, Yamahara J, Li Y: A 35-day gavage safety assessment of ginger in rats. Regul Toxicol Pharmacol. 2009, 54: 118-123. 10.1016/j.yrtph.2009.03.002.View ArticlePubMedPubMed CentralGoogle Scholar
- Tappy L, Lê KA: Metabolic effects of fructose and the worldwide increase in obesity. Phys Rev. 2010, 90: 23-46. 10.1152/physrev.00019.2009.Google Scholar
- Liu C, Li Y, Zuo G, Xu W, Gao H, Yang Y, Yamahara J, Wang J, Li Y: Oleanolic acid diminishes liquid fructose-induced fatty liver in rats: role of modulation of hepatic sterol regulatory element-binding protein 1c-mediated expression of genes responsible for de novo fatty acid synthesis. Evid-Based Complement Alternat Med. 2013, 2013: 534084-PubMedPubMed CentralGoogle Scholar
- Liu L, Yang M, Lin X, Li Y, Liu C, Yang Y, Yamahara J, Wang J, Li Y: Modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to Salacia oblonga root-elicited improvement of fructose-induced fatty liver in rats. J Ethnopharmacol. 2013, 150: 1045-1052. 10.1016/j.jep.2013.10.020.View ArticlePubMedGoogle Scholar
- Madkor HR, Mansour SW, Ramadan G: Modulatory effects of garlic, ginger, turmeric and their mixture on hyperglycaemia, dyslipidaemia and oxidative stress in streptozotocin-nicotinamide diabetic rats. Br J Nutr. 2011, 105: 1210-1217. 10.1017/S0007114510004927.View ArticlePubMedGoogle Scholar
- Al-Amin ZM, Thomson M, Al-Qattan KK, Peltonen-Shalaby R, Ali M: Anti-diabetic and hypolipidaemic properties of ginger (Zingiber officinale) in streptozotocin-induced diabetic rats. Br J Nutr. 2006, 96: 660-666. 10.1079/BJN20061849.View ArticlePubMedGoogle Scholar
- Goor HV, Ding G, Kees-Folts D, Grond J, Schreiner GF, Diamond JR: Macrophages and renal disease. Lab Invest. 1994, 71: 456-464.PubMedGoogle Scholar
- Eardley KS, Cockwell P: Macrophages and progressive tubulointerstitial disease. Kidney Int. 2005, 68: 437-455. 10.1111/j.1523-1755.2005.00422.x.View ArticleGoogle Scholar
- Cirillo P, Gersch MS, Mu W, Scherer PM, Kim KM, Gesualdo L, Henderson GN, Johnson RJ, Sautin YY: Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J Am Soc Nephrol. 2009, 20: 545-553. 10.1681/ASN.2008060576.View ArticlePubMedPubMed CentralGoogle Scholar
- Furuichi K, Wada T, Iwata Y, Kitagawa K, Kobayashi K, Hashimoto H, Ishiwata Y, Asano M, Wang H, Matsushima K, Takeya M, Kuziel WA, Mukaida N, Yokoyama H: CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol. 2003, 14: 2503-2515. 10.1097/01.ASN.0000089563.63641.A8.View ArticlePubMedGoogle Scholar
- Grandaliano G, Gesualdo L, Ranieri E, Monno R, Montinaro V, Marra F, Schena FP: Monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: a pathogenetic role in interstitial monocytes recruitment. J Am Soc Nephrol. 1996, 7: 906-913.PubMedGoogle Scholar
- Eardley KS, Zehnder D, Quinkler M, Lepenies J, Bates RL, Savage CO, Howie AJ, Adu D, Cockwell P: The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease. Kidney Int. 2006, 69: 1189-1197. 10.1038/sj.ki.5000212.View ArticlePubMedGoogle Scholar
- Galkina E, Ley K: Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol. 2006, 17: 368-377. 10.1681/ASN.2005080859.View ArticlePubMedGoogle Scholar
- Guo G, Morrissey J, McCracken R, Tolley T, Liapis H, Klahr S: Contributions of angiotensin II and tumor necrosis factor-alpha to the development of renal fibrosis. Am J Physiol Renal Physiol. 2001, 280: F777-F785.PubMedGoogle Scholar
- Tripathi S, Maier KG, Bruch D, Kittur DS: Effect of 6-gingerol on pro-inflammatory cytokine production and costimulatory molecule expression in murine peritoneal macrophages. J Surg Res. 2007, 138: 209-213. 10.1016/j.jss.2006.07.051.View ArticlePubMedGoogle Scholar
- Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S, Korlakunta JN: Comparative antioxidant and anti-inflammatory effects of -gingerol, -gingerol, -gingerol and -shogaol. J Ethnopharmacol. 2010, 127: 515-520. 10.1016/j.jep.2009.10.004.View ArticlePubMedGoogle Scholar
- Shim S, Kim S, Choi DS, Kwon YB, Kwon J: Anti-inflammatory effects of -shogaol: potential roles of HDAC inhibition and HSP70 induction. Food Chem Toxicol. 2011, 49: 2734-2740. 10.1016/j.fct.2011.08.012.View ArticlePubMedGoogle Scholar
- Lee HY, Park SH, Lee M, Kim HJ, Ryu SY, Kim ND, Hwang BY, Hong JT, Han SB, Kim Y: 1-Dehydro--gingerdione from ginger inhibits IKKβ activity for NF-κB activation and suppresses NF-κB-regulated expression of inflammatory genes. Br J Pharmacol. 2012, 167: 128-140. 10.1111/j.1476-5381.2012.01980.x.View ArticlePubMedPubMed CentralGoogle Scholar
- Woo HM, Kang JH, Kawada T, Yoo H, Sung MK, Yu R: Active spice-derived components can inhibit inflammatory responses of adipose tissue in obesity by suppressing inflammatory actions of macrophages and release of monocyte chemoattractant protein-1 from adipocytes. Life Sci. 2007, 80: 926-931. 10.1016/j.lfs.2006.11.030.View ArticlePubMedGoogle Scholar
- Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM, Ranganathan G, Peterson CA, McGehee RE, Kern PA: Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes. 2005, 54: 2305-2313. 10.2337/diabetes.54.8.2305.View ArticlePubMedGoogle Scholar
- Galic S, Fullerton MD, Schertzer JD, Sikkema S, Marcinko K, Walkley CR, Izon D, Honeyman J, Chen ZP, Van Denderen BJ, Kemp BE, Steinberg GR: Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest. 2011, 121: 4903-4915. 10.1172/JCI58577.View ArticlePubMedPubMed CentralGoogle Scholar
- Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, Asano M, Takeya M, Kuziel WA, Matsushima K, Mukaida N, Yokoyama H: Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol. 2004, 165: 237-246. 10.1016/S0002-9440(10)63292-0.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhang XL, Topley N, Ito T, Phillips A: Interleukin-6 regulation of transforming growth factor (TGF)-beta receptor compartmentalization and turnover enhances TGF-beta1 signaling. J Biol Chem. 2005, 280: 12239-12245. 10.1074/jbc.M413284200.View ArticlePubMedGoogle Scholar
- Lund LR, Riccio A, Andreasen PA, Nielsen LS, Kristensen P, Laiho M, Saksela O, Blasi F, Danø K: Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen-activator inhibitor messenger-RNA in Wi-38 human lung fibroblasts. EMBO J. 1987, 6: 1281-1286.PubMedPubMed CentralGoogle Scholar
- Eddy AA: Plasminogen activator inhibitor-1 and the kidney. Am J Physiol. 2002, 283: F209-F220.Google Scholar
- Fogo AB: Renal fibrosis: not just PAI-1 in the sky. J Clin Invest. 2003, 112: 326-328. 10.1172/JCI19375.View ArticlePubMedPubMed CentralGoogle Scholar
- Deatrick KB, Eliason JL, Lynch EM, Moore AJ, Dewyer NA, Varma MR: Vein wall remodeling after deep vein thrombosis involves matrix metalloproteinases and late fibrosis in a mouse model. J Vasc Surg. 2005, 42: 140-148. 10.1016/j.jvs.2005.04.014.View ArticlePubMedGoogle Scholar
- Park SA, Park IH, Cho JS, Moon YM, Lee SH, Kim TH, Lee SH, Lee HM: Effect of -gingerol on myofibroblast differentiation in transforming growth factor beta 1-induced nasal polyp-derived fibroblasts. Am J Rhinol Allergy. 2012, 26: 97-103. 10.2500/ajra.2012.26.3736.View ArticlePubMedGoogle Scholar
- Kamato D, Babaahmadi Rezaei H, Getachew R, Thach L, Guidone D, Osman N, Roufogalis B, Duke CC, Tran VH, Zheng W, Little PJ: (S)--Gingerol inhibits TGF-β-stimulated biglycan synthesis but not glycosaminoglycan hyperelongation in human vascular smooth muscle cells. J Pharm Pharmacol. 2013, 65: 1026-1036. 10.1111/jphp.12060.View ArticlePubMedGoogle Scholar
- Bobulescu IA: Renal lipid metabolism and lipotoxicity. Curr Opin Nephrol Hypertens. 2010, 19: 393-402. 10.1097/MNH.0b013e32833aa4ac.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/14/174/prepub
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