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Pelajari lebih lanjut: Penafian PMC | Pemberitahuan Hak Cipta PMJ Biomed Sains. 2015; 22: 93.
Pelajari lebih lanjut: Penafian PMC | Pemberitahuan Hak Cipta PMJ Biomed Sains. 2015; 22: 93.
Diterbitkan online 22 Oktober 2015. doi: 10.1186/s12929-015-0192-5
PMCID: PMC4618747
PMID: 26493866
Kerusakan ginjal oksidatif yang diinduksi monosodium glutamat dan kemungkinan mekanismenya: tinjauan singkat
Abstrak
Penelitian pada hewan menunjukkan bahwa asupan monosodium glutamat (MSG) kronis menyebabkan kerusakan ginjal akibat stres oksidatif. Namun, mekanisme yang mendasarinya masih belum jelas, meskipun semakin banyak bukti dan konsensus bahwa α-ketoglutarate dehydrogenase, reseptor glutamat, dan antiporter sistin-glutamat memainkan peran penting dalam meningkatkan regulasi stres oksidatif pada toksisitas ginjal yang disebabkan oleh MSG. Tinjauan ini merangkum bukti dari penelitian terhadap kerusakan oksidatif ginjal akibat MSG, kemungkinan mekanismenya dan pentingnya hal tersebut dari sudut pandang toksikologi.
Kata Kunci: Monosodium glutamat, Ginjal, Stres oksidatif, Reseptor glutamat, α-Ketoglutarate dehydrogenase
Perkenalan
Monosodium glutamat (MSG) adalah bahan tambahan yang umum digunakan dalam makanan olahan dan masakan Asia untuk meningkatkan palatabilitas. Namun, beberapa penelitian pada hewan menunjukkan bahwa MSG bersifat racun bagi berbagai organ seperti hati, otak, timus, dan ginjal [ 1 – 3 ]. Data yang dipublikasikan menunjukkan bahwa fibrosis ginjal berhubungan dengan konsumsi MSG secara kronis [ 4 ] dan stres oksidatif adalah penyebab utama cedera ginjal [ 5 ].
Stres oksidatif disebabkan oleh produksi berlebihan atau penurunan eliminasi radikal bebas dalam sel, yang sebagian besar adalah radikal oksigen dan spesies oksigen reaktif (ROS) lainnya [ 6 ]. Metabolisme nutrisi dan beberapa faktor ekstraseluler dan intraseluler seperti hormon, sitokin, dan proses detoksifikasi berkontribusi terhadap stres oksidatif [ 7-9 ] . Oleh karena itu, metabolisme glutamat ginjal yang berlebihan seperti pada asupan MSG kronis dapat menjadi sumber ROS. Penurunan kadar enzim anti-oksidan utama dan peningkatan peroksidasi lipid telah ditunjukkan pada ginjal tikus kronis yang terpajan MSG [ 10 , 11 ]. Selain itu, glutamat dosis tinggi telah terbukti menyebabkan toksisitas yang signifikan pada sel kultur ginjal [ 12 ].
Banyaknya asam lemak tak jenuh ganda rantai panjang dalam komposisi lipid ginjal membuat ginjal rentan terhadap kerusakan akibat ROS [ 13 ]. Hal ini membuat jaringan ginjal rentan terhadap kerusakan akibat mekanisme yang berbeda seperti peningkatan peroksidasi lipid, modifikasi protein, dan kerusakan DNA. , menyebabkan kematian sel [ 14 – 16 ]. Oleh karena itu, keterlibatan ROS telah dilaporkan pada perubahan glomerulus, tubulus, dan tubulo-interstitial [ 17 , 18 ].
Sejumlah penelitian telah menjelaskan kerusakan oksidatif yang disebabkan oleh glutamat pada jaringan seperti otak atau neuron, di mana α-ketoglutarate dehydrogenase, reseptor glutamat, dan antiporter sistin-glutamat merupakan faktor penting [ 19 – 21 ]. Molekul-molekul ini dapat berkontribusi terhadap stres oksidatif melalui , mekanismenya berbeda tetapi sedikit yang diketahui tentang keterlibatannya dalam stres oksidatif ginjal yang disebabkan oleh MSG. Peningkatan kadar α-ketoglutarate dehydrogenase telah ditemukan di ginjal tikus yang diberi MSG [ 5 ] dan oleh karena itu, konsensus yang kuat sedang dikembangkan terhadap α-ketoglutarate dehydrogenase, reseptor glutamat, dan antiporter sistin-glutamat karena peran potensialnya dalam stres oksidatif ginjal terkait MSG. Tujuan dari tinjauan singkat ini adalah untuk menguraikan kerusakan ginjal oksidatif akibat MSG dan kemungkinan mekanismenya.
Tinjauan
Kerusakan ginjal akibat MSG
Hubungan antara faktor makanan, termasuk MSG dan risiko penyakit ginjal, telah dihipotesiskan dalam banyak penelitian. Ginjal sangat sensitif terhadap iskemia, racun, dan bahan kimia lainnya. Dengan demikian, proses yang menyebabkan gangguan langsung atau tidak langsung pada metabolisme energi sel ginjal akan mengakibatkan cedera sel dan insufisiensi ginjal akut [ 22 ].
Ringkasan perubahan ginjal kronik akibat MSG diilustrasikan pada Gambar. 1. MSG dapat menginduksi perubahan sitoarsitektur ginjal, meningkatkan hiperselularitas glomerulus, infiltrasi sel inflamasi pada korteks ginjal, edema sel tubulus, dan akhirnya degenerasi tubulus ginjal [ 10 , 11 , 23 ]. Meskipun infiltrasi sel inflamasi mengarah pada suatu patologi, patofisiologi pastinya belum sepenuhnya dipahami. Disfungsi seluler dianggap sebagai penyebab penting perkembangan selanjutnya dari sebagian besar perubahan morfologi, terlepas dari prinsip toksik yang bekerja pada ginjal. Oleh karena itu, pemeriksaan ultra-struktural ginjal pada model eksperimental dengan pengobatan MSG kronis dapat berkontribusi pada pemahaman yang lebih baik tentang mekanisme gangguan selama cedera ginjal.
Garis besar perubahan ginjal kronis akibat MSG pada ginjal. Urin yang bersifat basa dan stres oksidatif akibat asupan MSG kronis dapat merusak ginjal melalui mekanisme yang tidak diketahui. Urolitiasis juga dapat berkontribusi terhadap fibrosis interstisial dengan memproduksi sitokin inflamasi dan ROS
Bukti eksperimental kerusakan ginjal yang dimediasi oleh asupan MSG kronis akan dibahas lebih lanjut dalam stres oksidatif, urolitiasis, dan fibrosis interstisial.
Stres oksidatif
Pembentukan ROS di ginjal yang terpapar MSG dipandang sebagai kontributor utama efek nefrotoksik yang menyebabkan kerusakan seluler dan fungsional [ 24 ]. Suplementasi MSG baik melalui suntikan atau asupan oral telah terbukti mengubah penanda sistem antioksidan ginjal, termasuk produk sampingan peroksidasi lipid dan fungsi ginjal pada tikus [ 10 , 24 ]. Paulus dkk. (2012) menemukan penurunan aktivitas superoksida dismutase, katalase, glutathione-S-transferase dan glutathione (GSH) di ginjal setelah pemberian MSG [ 10 ]. Mereka juga melaporkan bahwa penanda peroksidasi lipid seperti malondialdehyde (MDA) dan diena terkonjugasi meningkat pada jaringan ginjal yang diberi MSG. Ada kemungkinan bahwa MSG menyebabkan produksi radikal bebas yang berlebihan dan antioksidan endogen tidak cukup untuk memenuhi permintaan. Peningkatan regulasi heat shock serumpun 70, sebuah indikator stres oksidatif, dan penurunan regulasi glutathione-S-transferase pada ginjal yang diberi MSG semakin memperkuat temuan ini [ 5 ]. Selain itu, beberapa penelitian telah menemukan efek perbaikan vitamin C, E, dan quercetin pada ginjal yang diobati dengan MSG [ 2 , 10 ]. Mekanisme bagaimana antioksidan ini memberikan efek tersebut masih belum sepenuhnya dijelaskan. Namun, antioksidan ini tampaknya memainkan peran kunci terhadap respon inflamasi ginjal melalui penurunan aktivitas enzim inflamasi [ 25 ] dan sekresi sitokin, atau dengan menghambat aktivitas NF-ĸB [ 26 , 27 ].
Selain itu, penelitian yang menggunakan antioksidan tiol seperti N-asetilsistein (NAC) dan asam lipoat telah menunjukkan perlindungan terapeutik terhadap neurotoksisitas yang diinduksi glutamat [ 28 , 29 ]. Meskipun tidak ada bukti eksperimental yang mendukung efek perlindungan molekul-molekul ini pada toksisitas oksidatif ginjal yang diinduksi MSG, NAC telah terbukti mengurangi kadar MDA ginjal pada model tikus diabetes [ 30 ]. Dalam kultur sel epitel tubulus proksimal manusia, NAC mengurangi peroksidasi lipid dan mempertahankan potensi membran mitokondria, sehingga mencegah apoptosis setelah pemberian hidrogen peroksida [ 31 ]. Selain itu, asam lipoat telah efektif dalam melindungi ginjal dari stres oksidatif dan disfungsi mitokondria [ 32 ]. Dalam konteks yang berbeda, efek perbaikan selenium terhadap toksisitas oksidatif testis yang diinduksi MSG telah dibuktikan [ 33 ]. Temuan penting ini menambah prospek lebih lanjut terhadap terapi stres oksidatif ginjal yang diinduksi MSG dengan menggunakan antioksidan.
Urolitiasis dan fibrosis interstisial
Nefropati obstruktif akibat diet MSG kronis telah dilaporkan pada tikus dewasa mungkin karena urin bersifat basa dan penurunan kadar penghambat batu seperti magnesium dan sitrat dalam urin [ 4 ]. Mekanisme dibalik alkalisasi urin akibat MSG masih belum diketahui namun efek ini pertama kali dilaporkan oleh de Groot dkk. (1988) [ 34 ]. Kemungkinan besar hewan yang diberi MSG dapat menghasilkan produk katabolik glutamat yang lebih tinggi di sel ginjal dan kerangka karbonnya diubah menjadi karbon dioksida dan kemudian menjadi anion bikarbonat [ 35 , 36 ]. Bikarbonat yang dihasilkan kemudian diserap kembali ke dalam sirkulasi darah dan akhirnya ke ginjal untuk ekskresi ekstra-alkali, menghasilkan urin yang bersifat basa [ 37 , 38 ]. Urine yang bersifat basa dapat mempengaruhi kapasitas ginjal dalam hal mensekresi atau menyerap kembali metabolit yang dapat berkontribusi terhadap pembentukan batu, sedangkan penghambat pembentukan batu berperan besar dalam pertahanan alami. Peningkatan aktivitas ion produk kalsium fosfat dalam urin basa tikus yang diberi MSG menunjukkan risiko pembentukan batu kalsium-fosfat [ 4 ].
Lebih lanjut, ROS dapat menyebabkan kerusakan pada sel yang menyebabkan kematian sel dan pembentukan vesikel terikat membran yang mendukung nukleasi kristal [ 39 , 40 ]. Dengan latar belakang ini, hidronefrosis dengan perubahan besar seperti fibrosis pada kompartemen tubulo-interstisial telah dilaporkan pada ginjal tikus yang diberi MSG oleh Sharma dkk. (2013) [ 4 ]. Penting untuk dicatat di sini bahwa 2/10 hewan yang diberi MSG menunjukkan adanya hidronefrosis dan 3/10 menunjukkan batu ginjal dalam penelitian ini. Namun, semua tikus yang diobati dengan MSG mempunyai tingkat fibrosis ginjal yang sangat tinggi dibandingkan dengan tikus kontrol, hal ini menunjukkan adanya efek fibrotik dari MSG, bukan hanya obstruksi ginjal. Sulit untuk menjelaskan perbedaan temuan ini pada hewan yang diberi MSG, namun faktor individual mungkin berperan. Dalam percobaan yang berbeda, kelompok kami tidak dapat melihat perubahan fungsi ginjal atau batu pada tikus pada 1 bulan, 3 bulan, dan 6 bulan pengobatan MSG (data tidak dipublikasikan). Namun, perubahan fungsi dan patologi ginjal tetapi bukan batu ginjal dilaporkan oleh Paul dkk. (2012) setelah 6 bulan pengobatan MSG oral dengan dosis lebih tinggi. Hal ini menunjukkan bahwa dosis dan durasi paparan MSG sangat penting untuk efek nefrotoksiknya termasuk batu dan obstruksi.
Gangguan mekanis akibat obstruksi ureter total menyebabkan cedera tubulus, mengakibatkan sitokin pro-inflamasi dan fibrosis tubulo-interstitial [ 41 ]. Oleh karena itu, dalam percobaan dengan model tikus yang mengalami penyumbatan ureter, para peneliti menemukan peningkatan pewarnaan 4-hidroksinoneal (4-HNE) untuk produk ROS di kompartemen tubulo-interstitial ginjal [ 42 ]. Oleh karena itu dapat diduga bahwa urolitiasis dan stres oksidatif akibat MSG dapat menyebabkan fibrosis pada ginjal, karena ROS dapat menginduksi transformasi fibroblas menjadi myofibroblast [ 43 ]. Fibrosis interstisial tubular sangat terkait dengan perkembangan penyakit ginjal [ 44 ].
Pembentukan ROS yang diinduksi MSG di ginjal
Kemungkinan mekanisme produksi ROS yang diinduksi MSG di ginjal diilustrasikan pada Gambar. 2. ROS arises as a by-product of aerobic metabolism [45]. The main sites of ROS production are the mitochondrial electron transport system, peroxisomal fatty acid, cytochrome P-450, and phagocytic cells [46, 47]. One study suggested that the mitochondrial electron transport chain is a major source of ROS in oxidative glutamate toxicity [48] and that extracellular glutamate level increases the formation of hydroxyl radicals [49]. Most cellular ROS arise due to leakage of electrons from the mitochondrial respiratory chain. In normal physiological conditions, ROS produced as a byproduct of metabolic processes are completely inactivated by cellular and extracellular defense mechanisms. Nutrient metabolism can affect the production of oxidative stress in the kidney by altering energy metabolism. In this scenario, α-ketoglutarate dehydrogenase (α -KGDH) is the primary site of the control of the metabolic flux through the Krebs cycle [50].
A proposed model of MSG-induced ROS production in the rat kidney. Glutamate upon chronic MSG exposure may raise the activity of α-ketoglutarate dehydrogenase, a potential ROS generator. Additionally, an increased intracellular calcium level via glutamate receptors can stimulate free radical generation and lipid peroxidation. Inhibition of cystine uptake leads to decreased GSH levels that may further promote ROS-mediated renal cell damage
α-Ketoglutarate dehydrogenase: an ROS generator
A recent study has shown that increased activity of α-KGDH is related to the glutamate-stimulated ROS production in rat kidneys [5]. According to this study, glutamate contributes fuel to the Krebs cycle and modulates the redox state of the cell. High glutamate concentration may increase the mitochondrial proton gradient as a result of the over production of the electron donor by the Krebs cycle, which may in turn increase the production of mitochondrial superoxide. This proposed mechanism is supported by evidence from brain tissues where α-KGDH is a potential site of ROS generation against glutamate [21]. The E3 subunit (lipoamide dehydrogenase) of α-KGDH can activate oxygen, resulting in the production of superoxide and/or hydrogen peroxide [51–53].
α-KGDH is a key and arguably the rate-limiting enzyme in the Krebs cycle. The enzyme is inhibited by its own product, succinyl-CoA, or by a high NADH/NAD+ ratio, as well as by a high dihydrolipoate/lipoate ratio, thereby playing an important role in cellular redox regulation [52, 54]. However, an increased level of succinyl CoA ligase in the MSG-treated kidney tissue [5] may favor the activation of α-KGDH by consuming succinyl CoA, an inhibitor. In addition, during the oxidative stress a segment of the Krebs cycle is maintained by glutamate through α-ketoglutarate [55]. Increased levels of glyceraldehyde-3-phosphate dehydrogenase as reported in MSG treated kidney [5] can also cause oxidative stress because isolated glyceraldehyde-3-phosphate dehydrogenase has been shown to catalyze NADH-dependent superoxide production [56]. Notably, NADH is one of the regulators for the activity of α-KGDH. It is possible that the excessive metabolism of glutamate in the kidney wards off the barriers to α-KGDH and thus changes the redox state of the cell. Further studies exploring the relationship between energy metabolism and oxidative stress in MSG-treated kidneys are necessary to elucidate this phenomenon.
Glutamate receptors
Most studies in the literature link oxidative stress and tissue damage through glutamate receptor (N-methyl –D- aspartate, NMDA) via calcium (Ca2+) in MSG-induced renal toxicity. There are two categories of receptors available to glutamate: ionotropic and metabotropic receptors [57]. Nearly all of the known glutamate receptors and many of their interacting proteins have been detected in the kidney [58–60]. Most of the functional studies of the kidney have examined NMDA receptors, a subtype of ionotropic receptor, and group 1 metabotropic glutamate receptors (mGluRs).
NMDA receptors are Ca2+ favoring glutamate gated ion channels, whereas mGluRs are coupled to G protein cascades [19, 61]. The functional significance of these receptors for normal kidney physiology is not well understood. But, increased NMDA receptor subunit NR1 and NR2C expression correlates with the renal damage in a rat model of gentamicin nephrotoxicity [62]. Furthermore, a study applying NMDA receptor agonists (glycine, glutamate) and antagonists (MK 801, CPP) in renal culture cells has demonstrated that an excessive stimulation or blockade of the renal NMDA receptor results in cell death [12]. Sustained activation of these receptors induces changes in cellular Ca2+ dynamics that can trigger numerous cellular reactions, including the activation of nitric oxide synthase and protein kinase C [63, 64]. These in turn can activate free radical generation and lipid peroxidation [65], leading to cell damage. This mechanism of excitotoxicity has been described not only in neurons but also in lung [19, 64]. However, there is no direct evidence in the literature of studies investigating the role of glutamate receptors against MSG-induced renal cell damage; experiments with the blockade of NMDA receptor to prevent MSG-induced toxicity could be conclusive.
Cystine-glutamate antiporter
The cystine-glutamate antiporter, designated as system xc-, exchanges extracellular cystine for intracellular glutamate in a variety of cells [66]. The uptake of cystine that results from cystine-glutamate exchange is critical in maintaining the levels of glutathione, a critical antioxidant [67]. Under the condition of oxidative stress, the transport activity of this carrier appears to be up-regulated [68, 69].
Considering the fact that the system xc- is strongly expressed in the kidney [70] and the decreased GSH levels are prominent in MSG-induced renal toxicity, our group investigated the expression level of system xc- in acute and chronic MSG-treated kidney. However, no significant changes were observed at the mRNA level (unpublished data). Notably, there are other minor transporters for cystine intake into the cell as well. In another study, marked inhibition of cystine uptake by glutamate in the five-day-cultured renal tubule cells of rats but not in uncultured cells has been observed [71]. Despite these findings, more studies are necessary to find the possible involvement of cystine-glutamate antiporter in MSG-induced oxidative kidney damage. It is important to note here that glutamate toxicity in the neuronal cells involves the inhibition of system xc-, leading to oxidative stress [20].
Conclusions
During the last decade it became apparent that the chronic intake of MSG has potential effects on the peripheral organs such as the kidneys. Reduced antioxidant enzymes, increased lipid peroxidation, and tubulo-interstitial fibrosis brought on by high MSG intake strongly support the theory that oxidative stress is central to MSG-induced renal toxicity, with α-KGDH as a key player. Also, there is now evidence that excessive NMDA receptor activation is toxic for renal cells. However, a more clear association has to be established between α-KGDH, glutamate receptors, cystine-glutamate antiporter, and chronic MSG intake in order to provide a more comprehensive mechanism of renal oxidative stress. Approaches utilizing high throughput in vitro methods are crucial.
Acknowledgements
The author would like to thank Assistant Professor Ubon Cha’on, Associate Professor Vitoon Prasongwattana and Associate Professor Sirirat Reungjui, faculty of medicine, Khon Kaen University, Thailand for their valuable comments during the editing of the manuscript. Special thanks to Dr. Namraj Goire for reviewing the manuscript.
Abbreviations
| GSH | Glutathione |
| HNE | Hydroxynoneal |
| MDA | Malondialdehyde |
| MSG | Monosodium glutamate |
| NAC | N-acetylcysteine |
| NAD+ | Nicotinamide adenine dinucleotide |
| NMDA | N-methyl -D- aspartate |
| ROS | Reactive oxygen species |
| α-KGDH | α-Ketoglutarate dehydrogenase |
Footnotes
Competing interests
The author declares that he has no competing interests.
Author’s contributions
AS conceptualized and wrote the manuscript.
Author’s information
AS is currently a post-doctoral researcher at Siriraj hospital, faculty of medicine, Mahidol University, Thailand. AS has more than three years of experience during his doctorate degree at Khon Kaen University, Thailand, in working with MSG associated renal effects in rats. AS and his colleagues has published articles reporting MSG induced kidney damage and oxidative stress in PLoS ONE.
References
1. Diniz YS, Fernandes AA, Campos KE, Mani F, Ribas BO, Novelli EL. Toxicity of hypercaloric diet and monosodium glutamate: oxidative stress and metabolic shifting in hepatic tissue. Food Chem Toxicol. 2004;42(2):313–319. doi: 10.1016/j.fct.2003.09.006. [PubMed] [CrossRef] [Google Scholar]
2. Farombi EO, Onyema OO. Monosodium glutamate-induced oxidative damage and genotoxicity in the rat: modulatory role of vitamin C, vitamin E and quercetin. Hum Exp Toxicol. 2006;25(5):251–259. doi: 10.1191/0960327106ht621oa. [PubMed] [CrossRef] [Google Scholar]
3. Pavlovic V, Pavlovic D, Kocic G, Sokolovic D, Sarac M, Jovic Z. Ascorbic acid modulates monosodium glutamate induced cytotoxicity in rat thymus. Bratisl Lek Listy. 2009;110(4):205–209. [PubMed] [Google Scholar]
4. Sharma A, Prasongwattana V, Cha'on U, Selmi C, Hipkaeo W, Boonnate P, et al. Monosodium glutamate (MSG) consumption is associated with urolithiasis and urinary tract obstruction in rats. PLoS One. 2013;8(9):e75546. doi: 10.1371/journal.pone.0075546. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
5. Sharma A, Wongkham C, Prasongwattana V, Boonnate P, Thanan R, Reungjui S, et al. Proteomic analysis of kidney in rats chronically exposed to monosodium glutamate. PLoS One. 2014;9(12):e116233. doi: 10.1371/journal.pone.0116233. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
6. Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev. 2009;89(1):27–71. doi: 10.1152/physrev.00014.2008. [PubMed] [CrossRef] [Google Scholar]
7. Corda S, Laplace C, Vicaut E, Duranteau J. Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol. 2001;24(6):762–768. doi: 10.1165/ajrcmb.24.6.4228. [PubMed] [CrossRef] [Google Scholar]
8. Stankiewicz A, Skrzydlewska E, Makiela M. Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats. Drug Metabol Drug Interact. 2002;19(2):67–82. doi: 10.1515/DMDI.2002.19.2.67. [PubMed] [CrossRef] [Google Scholar]
9. Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science. 1995;270(5234):296–299. doi: 10.1126/science.270.5234.296. [PubMed] [CrossRef] [Google Scholar]
10. Paul MV, Abhilash M, Varghese MV, Alex M, Nair RH. Protective effects of alpha-tocopherol against oxidative stress related to nephrotoxicity by monosodium glutamate in rats. Toxicol Mech Methods. 2012;22(8):625–630. doi: 10.3109/15376516.2012.714008. [PubMed] [CrossRef] [Google Scholar]
11. Thomas M, Sujatha KS, George S. Protective effect of Piper longum Linn. on monosodium glutamate induced oxidative stress in rats. Indian J Exp Biol. 2009;47(3):186–192. [PubMed] [Google Scholar]
12. Leung JC, Ragland N, Marphis T, Silverstein DM. NMDA agonists and antagonists induce renal culture cell toxicity. Med Chem. 2008;4(6):565–571. doi: 10.2174/157340608786242034. [PubMed] [CrossRef] [Google Scholar]
13. Kubo K, Saito M, Tadokoro T, Maekawa A. Changes in susceptibility of tissues to lipid peroxidation after ingestion of various levels of docosahexaenoic acid and vitamin E. Br J Nutr. 1997;78(4):655–669. doi: 10.1079/BJN19970181. [PubMed] [CrossRef] [Google Scholar]
14. Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A. 1988;85(17):6465–6467. doi: 10.1073/pnas.85.17.6465. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
15. Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, et al. Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. J Biol Chem. 1994;269(42):26066–26075. [PubMed] [Google Scholar]
16. Stadtman ER, Levine RL. Protein oxidation. Ann N Y Acad Sci. 2000;899:191–208. doi: 10.1111/j.1749-6632.2000.tb06187.x. [PubMed] [CrossRef] [Google Scholar]
17. Klahr S. Oxygen radicals and renal diseases. Miner Electrolyte Metab. 1997;23(3–6):140–143. [PubMed] [Google Scholar]
18. Vielhauer V, Anders HJ, Mack M, Cihak J, Strutz F, Stangassinger M, et al. Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes. J Am Soc Nephrol. 2001;12(6):1173–1187. [PubMed] [Google Scholar]
19. Jahr CE, Stevens CF. Calcium permeability of the N-methyl-D-aspartate receptor channel in hippocampal neurons in culture. Proc Natl Acad Sci U S A. 1993;90(24):11573–11577. doi: 10.1073/pnas.90.24.11573. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron. 1989;2(6):1547–1558. doi: 10.1016/0896-6273(89)90043-3. [PubMed] [CrossRef] [Google Scholar]
21. Zundorf G, Kahlert S, Bunik VI, Reiser G. alpha-Ketoglutarate dehydrogenase contributes to production of reactive oxygen species in glutamate-stimulated hippocampal neurons in situ. Neuroscience. 2009;158(2):610–616. doi: 10.1016/j.neuroscience.2008.10.015. [PubMed] [CrossRef] [Google Scholar]
22. Pfaller W, Gstraunthaler G, Willinger CC. Morphology of renal tubular damage from nephrotoxins. Toxicol Lett. 1990;53(1–2):39–43. doi: 10.1016/0378-4274(90)90092-Z. [PubMed] [CrossRef] [Google Scholar]
23. Dixit SG, Rani P, Anand A, Khatri K, Chauhan R, Bharihoke V. To study the effect of monosodium glutamate on histomorphometry of cortex of kidney in adult albino rats. Ren Fail. 2014;36(2):266–270. doi: 10.3109/0886022X.2013.846865. [PubMed] [CrossRef] [Google Scholar]
24. Ortiz GG, Bitzer-Quintero OK, Zarate CB, Rodriguez-Reynoso S, Larios-Arceo F, Velazquez-Brizuela IE, et al. Monosodium glutamate-induced damage in liver and kidney: a morphological and biochemical approach. Biomed Pharmacother. 2006;60(2):86–91. doi: 10.1016/j.biopha.2005.07.012. [PubMed] [CrossRef] [Google Scholar]
25. Ozaki M, Yamada Y, Matoba K, Otani H, Mune M, Yukawa S, et al. Phospholipase A2 activity in ox-LDL-stimulated mesangial cells and modulation by alpha-tocopherol. Kidney Int Suppl. 1999;71:S171–S173. doi: 10.1046/j.1523-1755.1999.07144.x. [PubMed] [CrossRef] [Google Scholar]
26. Bowie AG, O'Neill LA. Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol. 2000;165(12):7180–7188. doi: 10.4049/jimmunol.165.12.7180. [PubMed] [CrossRef] [Google Scholar]
27. Massy ZA, Guijarro C, O'Donnell MP, Kim Y, Kashtan CE, Egido J, et al. The central role of nuclear factor-kappa B in mesangial cell activation. Kidney Int Suppl. 1999;71:S76–S79. doi: 10.1046/j.1523-1755.1999.07119.x. [PubMed] [CrossRef] [Google Scholar]
28. Han D, Sen CK, Roy S, Kobayashi MS, Tritschler HJ, Packer L. Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants. Am J Physiol. 1997;273(5 Pt 2):R1771–R1778. [PubMed] [Google Scholar]
29. Penugonda S, Ercal N. Comparative evaluation of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) on glutamate and lead-induced toxicity in CD-1 mice. Toxicol Lett. 2011;201(1):1–7. doi: 10.1016/j.toxlet.2010.11.013. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
30. Ribeiro G, Roehrs M, Bairros A, Moro A, Charao M, Araujo F, et al. N-acetylcysteine on oxidative damage in diabetic rats. Drug Chem Toxicol. 2011;34(4):467–474. doi: 10.3109/01480545.2011.564179. [PubMed] [CrossRef] [Google Scholar]
31. Ye J, Li J, Yu Y, Wei Q, Deng W, Yu L. L-carnitine attenuates oxidant injury in HK-2 cells via ROS-mitochondria pathway. Regul Pept. 2010;161(1–3):58–66. doi: 10.1016/j.regpep.2009.12.024. [PubMed] [CrossRef] [Google Scholar]
32. Cimolai MC, Vanasco V, Marchini T, Magnani ND, Evelson P, Alvarez S. alpha-Lipoic acid protects kidney from oxidative stress and mitochondrial dysfunction associated to inflammatory conditions. Food Function. 2014;5(12):3143–3150. doi: 10.1039/C4FO00489B. [PubMed] [CrossRef] [Google Scholar]
33. Hamza RZ, Al-Harbi MS. Monosodium glutamate induced testicular toxicity and the possible ameliorative role of vitamine E or selenium in male rats. Toxicol Rep. 2014;1:1037–1045. doi: 10.1016/j.toxrep.2014.10.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. de Groot AP, Feron VJ, Immel HR. Induction of hyperplasia in the bladder epithelium of rats by a dietary excess of acid or base: implications for toxicity/carcinogenicity testing. Food Chem Toxicol. 1988;26(5):425–434. doi: 10.1016/0278-6915(88)90053-1. [PubMed] [CrossRef] [Google Scholar]
35. Stegink LD, Brummel MC, Boaz DP, Filer LJ., Jr Monosodium glutamate metabolism in the neonatal pig: conversion of administered glutamate into other metabolites in vivo. J Nutr. 1973;103(8):1146–1154. [PubMed] [Google Scholar]
36. Vercoutere B, Durozard D, Baverel G, Martin G. Complexity of glutamine metabolism in kidney tubules from fed and fasted rats. Biochem J. 2004;378(Pt 2):485–495. doi: 10.1042/bj20031088. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Hediger MA. Glutamate transporters in kidney and brain. Am J Physiol. 1999;277(4 Pt 2):F487–F492. [PubMed] [Google Scholar]
38. Vinay P, Lemieux G, Gougoux A, Halperin M. Regulation of glutamine metabolism in dog kidney in vivo. Kidney Int. 1986;29(1):68–79. doi: 10.1038/ki.1986.9. [PubMed] [CrossRef] [Google Scholar]
39. Khan SR, Glenton PA, Backov R, Talham DR. Presence of lipids in urine, crystals and stones: implications for the formation of kidney stones. Kidney Int. 2002;62(6):2062–2072. doi: 10.1046/j.1523-1755.2002.00676.x. [PubMed] [CrossRef] [Google Scholar]
40. Talham DR, Backov R, Benitez IO, Sharbaugh DM, Whipps S, Khan SR. Role of lipids in urinary stones: studies of calcium oxalate precipitation at phospholipid langmuir monolayers. Langmuir. 2006;22(6):2450–2456. doi: 10.1021/la052503u. [PubMed] [CrossRef] [Google Scholar]
41. Ricardo SD, Diamond JR. The role of macrophages and reactive oxygen species in experimental hydronephrosis. Semin Nephrol. 1998;18(6):612–621. [PubMed] [Google Scholar]
42. Yeh CH, Chiang HS, Lai TY, Chien CT. Unilateral ureteral obstruction evokes renal tubular apoptosis via the enhanced oxidative stress and endoplasmic reticulum stress in the rat. Neurourol Urodyn. 2011;30(3):472–479. doi: 10.1002/nau.20855. [PubMed] [CrossRef] [Google Scholar]
43. Sampson N, Koziel R, Zenzmaier C, Bubendorf L, Plas E, Jansen-Durr P, et al. ROS signaling by NOX4 drives fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma. Mol Endocrinol. 2011;25(3):503–515. doi: 10.1210/me.2010-0340. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Barnes JL, Gorin Y. Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 2011;79(9):944–956. doi: 10.1038/ki.2010.516. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
45. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993;262(5134):689–695. doi: 10.1126/science.7901908. [PubMed] [CrossRef] [Google Scholar]
46. Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science. 2003;299(5613):1751–1753. doi: 10.1126/science.1080418. [PubMed] [CrossRef] [Google Scholar]
47. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78(2):547–581. [PubMed] [Google Scholar]
48. Tan S, Sagara Y, Liu Y, Maher P, Schubert D. The regulation of reactive oxygen species production during programmed cell death. J Cell Biol. 1998;141(6):1423–1432. doi: 10.1083/jcb.141.6.1423. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
49. Yang CS, Tsai PJ, Lin NN, Liu L, Kuo JS. Elevated extracellular glutamate levels increased the formation of hydroxyl radical in the striatum of anesthetized rat. Free Radic Biol Med. 1995;19(4):453–459. doi: 10.1016/0891-5849(95)00042-V. [PubMed] [CrossRef] [Google Scholar]
50. Hansford RG. Control of mitochondrial substrate oxidation. Curr Top Bioenerg. 1980;10:217–278. [Google Scholar]
51. Massey V. Activation of molecular oxygen by flavins and flavoproteins. J Biol Chem. 1994;269(36):22459–22462. [PubMed] [Google Scholar]
52. Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, et al. Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci. 2004;24(36):7779–7788. doi: 10.1523/JNEUROSCI.1899-04.2004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
53. Tretter L, Adam-Vizi V. Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2335–2345. doi: 10.1098/rstb.2005.1764. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
54. Bunik VI. 2-Oxo acid dehydrogenase complexes in redox regulation. Eur J Biochem. 2003;270(6):1036–1042. doi: 10.1046/j.1432-1033.2003.03470.x. [PubMed] [CrossRef] [Google Scholar]
55. Yudkoff M, Nelson D, Daikhin Y, Erecinska M. Tricarboxylic acid cycle in rat brain synaptosomes. Fluxes and interactions with aspartate aminotransferase and malate/aspartate shuttle. J Biol Chem. 1994;269(44):27414–27420. [PubMed] [Google Scholar]
56. Chan PC, Bielski BH. Glyceraldehyde-3-phosphate dehydrogenase-catalyzed chain oxidation of reduced nicotinamide adenine dinucleotide by perhydroxyl radicals. J Biol Chem. 1980;255(3):874–876. [PubMed] [Google Scholar]
57. Willard SS, Koochekpour S. Glutamate, glutamate receptors, and downstream signaling pathways. Int J Biol Sci. 2013;9(9):948–959. doi: 10.7150/ijbs.6426. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Gu L, Liang X, Wang L, Yan Y, Ni Z, Dai H, et al. Functional metabotropic glutamate receptors 1 and 5 are expressed in murine podocytes. Kidney Int. 2012;81(5):458–468. doi: 10.1038/ki.2011.406. [PubMed] [CrossRef] [Google Scholar]
59. Puliti A, Rossi PI, Caridi G, Corbelli A, Ikehata M, Armelloni S, et al. Albuminuria and glomerular damage in mice lacking the metabotropic glutamate receptor 1. Am J Pathol. 2011;178(3):1257–1269. doi: 10.1016/j.ajpath.2010.11.050. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
60. Rastaldi MP, Armelloni S, Berra S, Calvaresi N, Corbelli A, Giardino LA, et al. Glomerular podocytes contain neuron-like functional synaptic vesicles. FASEB J. 2006;20(7):976–978. doi: 10.1096/fj.05-4962fje. [PubMed] [CrossRef] [Google Scholar]
61. Aramori I, Nakanishi S. Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron. 1992;8(4):757–765. doi: 10.1016/0896-6273(92)90096-V. [PubMed] [CrossRef] [Google Scholar]
62. Leung JC, Marphis T, Craver RD, Silverstein DM. Altered NMDA receptor expression in renal toxicity: Protection with a receptor antagonist. Kidney Int. 2004;66(1):167–176. doi: 10.1111/j.1523-1755.2004.00718.x. [PubMed] [CrossRef] [Google Scholar]
63. Lan JY, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, et al. Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci. 2001;4(4):382–390. doi: 10.1038/86028. [PubMed] [CrossRef] [Google Scholar]
64. Said SI, Berisha HI, Pakbaz H. Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci U S A. 1996;93(10):4688–4692. doi: 10.1073/pnas.93.10.4688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
65. Babu GN, Bawari M, Ali MM. Lipid peroxidation potential and antioxidant status of circumventricular organs of rat brain following neonatal monosodium glutamate. Neurotoxicology. 1994;15(3):773–777. [PubMed] [Google Scholar]
66. Bridges R, Lutgen V, Lobner D, Baker DA. Thinking outside the cleft to understand synaptic activity: contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling. Pharmacol Rev. 2012;64(3):780–802. doi: 10.1124/pr.110.003889. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
67. Orrenius S, Ormstad K, Thor H, Jewell SA. Turnover and functions of glutathione studied with isolated hepatic and renal cells. Fed Proc. 1983;42(15):3177–3188. [PubMed] [Google Scholar]
68. Kim JY, Kanai Y, Chairoungdua A, Cha SH, Matsuo H, Kim DK, dkk. Pengangkut sistin/glutamat manusia: kloning dan peningkatan cDNA oleh stres oksidatif dalam sel glioma. Biochim Biophys Acta. 2001; 1512 (2):335–344. doi: 10.1016/S0005-2736(01)00338-8. [ PubMed ] [ CrossRef ] [ Google Cendekia ]
69. Miura K, Ishii T, Sugita Y, Bannai S. Serapan sistin dan tingkat glutathione dalam sel endotel yang terpapar stres oksidatif. Apakah J Fisiol. 1992; 262 (1 Pt 1):C50–C58. [ PubMed ] [ Google Cendekia ]
70. Burdo J, Dargusch R, Schubert D. Distribusi sistem antiporter sistin/glutamat xc- di otak, ginjal, dan duodenum. J Histokimia Sitokimia. 2006; 54 (5):549–557. doi: 10.1369/jhc.5A6840.2006. [ PubMed ] [ CrossRef ] [ Google Cendekia ]
71. Foreman JW, McNamara PD, Bowring MA, Lee J, Rea C, Segal S. Interaksi transpor sistin-glutamat dalam tubulus kortikal ginjal tikus, vesikel batas sikat, dan sel tubulus ginjal yang dikultur. Rep Biosci 1986; 6 (1):113–119. doi: 10.1007/BF01145186. [ PubMed ] [ CrossRef ] [ Google Cendekia ]
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