Research Progress of Astaxanthin on Contrast agent induced acute kidney injury

Dongmei Gao1 & Wenhua Li1,2*

1Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China

2Department of Cardiology, The Affiliated Hospital Of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China


Contrast agent induced acute kidney injury (CI-AKI) is a leading cause of hospital-acquired acute kidney injury as a result of more and more iodinated contrast-media use for diagnostic purposes. Previous studies have demonstrated that oxidative stress and apoptosis are established processes contributing to contrast agent induced acute kidney injury. Astaxanthin (ATX), a carotenoid found in microalgae, fungi, complex plants, seafood, flamingos and quail has been confirmed have anti-oxidant, and anti-apoptosis effects. Experimental investigations in a range of species using a contrast agent induced acute kidney injury model demonstrated kidney preservation when ATX is administered prior to the induction of contrast agent. ATX?as an natural antioxidant?is capable to prevent CI-AKI effectively?and the mechanism is possibly related to anti-oxidant and anti-apoptosis. In this mini review, we brie?y summarize the potential for ATX as a protector against CI-AKI pathologies.


Astaxanthin(ATX) is a xanthophyll carotenoid of predominantly marine origin, with potent antioxidant and anti-apoptosis effects demonstrated in both experimental and human studies. Many studies have proven that astaxanthin has a preventive effect on various kidney diseases1-5. Oxidative stress and apoptosis are common pathophysiological features of contrast agent induced acute kidney injury (CI-AKI)?hence ATX may have a potential therapeutic role in this condition. This review will summarize the available evidence suggesting ATX may be of therapeutic value in CI-AKI.

Oxidative stress damage is caused by an imbalance between oxidation and anti-oxidation in the body, which causes tissue damage caused by excessive generation of ROS and reactive nitrogen free radicals in the body. The appropriate amount of ROS can be used as a signal molecule to promote wound healing and tissue repair, reduce the production of malignant pathogens. On the contrary, excessive ROS can react with proteins, lipids, and DNA through a chain reaction, thereby destroying homeostasis and causing tissue damage6, 7. The exact mechanism of CIAKI is not fully understood. It has been suggested that CM increases osmotic load, decreases renal blood flow, and induces renal arterial constriction. Such a condition promotes generation of ROS and results in ischemic tubular injury, and can be a reason for direct tubular toxicity8, 9. Contrast agents make the imbalance between oxygen supply and demand, resulting in hypoxia of the medulla and hypoxic injury. A large number of animal experiments have found that after the use of contrast agents, the products of lipid peroxidation in animals will increase significantly, such as malondialdehyde and isoprostane. At the same time, a multiple increase in ROS can be detected in the urine of patients undergoing coronary angiography. ROS can prevent the vasodilatory effects of NO, resulting in ischemic injury and immune-mediated tissue damage10. After the angiography, hyperosmotic environment is formed outside the cell, and oxidative stress caused by ROS induces apoptosis of renal tubular epithelial cells.

ATX is well documented to have antioxidative activity as a scavenger of free radicals and a quencher of reactive oxygen species (ROS)11-13. The finding that spin trapping of ROS species by carotenoids, increases with increasing carotenoid oxidation potential14. That decreasing scavenging rate of free radicals decreases with decreasing oxidation potential. The oxidation potential of ATX being significantly higher than that of β-Carotene, thus the scavenging rate of ATX is much higher than that for β-Carotene and exhibits Pro-oxidative character which includes reduction of Fe3+ to Fe2+15, 16. The antioxidative activity of ATX on cells is greater than that of β-carotene, vitamin C, vitamin E, lutein, lycopene, and other catechins17, 18. Recently, Kim et al.19 suggested ATX effectively suppressed including lipid peroxidation, total reactive species (RS), superoxide (•O2), nitric oxide (NO•), and peroxynitrite (ONOO-). Studies have confirmed that the antioxidant activity of ATX plays a protective role in various kidney diseases. For instance, nephrotoxicity induced by CMS might be due to oxidative damage. The improvement by ATX is related to their antioxidant properties20. Pretreatment of ATX is effective in preserving renal function and histology against ischemia/reperfusion via antioxidant activity4.The nephrotoxic effect of cisplatin was diminished by the antioxidant effect of ATX21.ATX is useful for the prevention of Fe-NTA-induced renal tubular oxidative damage22.ATX plays an important role in reduction of oxidative damage and could prevent pathological changes in diabetic rats suggesting promising application of ATX in diabet treatment23. Thus, ATX provides protection against oxidative attacks in experimental renal diseases. We speculate that ATX has a protective effect on contrast, and its mechanism may be through antioxidant activity, and it has been verified in my previous experiment24.

Apoptosis is a process of programmed cell death that occurs in multicellular organisms. Caspase-3, a protease, is the most important terminal cleavage enzyme in apoptosis. Contrast medium (CM) induced renal epithelial cell apoptosis is an important underlying cause of renal failure25, 26. Previous studies have shown that CM induces apoptosis of tubular cells by activating intrinsic or mitochondrial pathway, which down-regulates anti-apoptotic genes and up-regulates pro-apoptotic genes. The expressions of apoptosis-related proteins such as caspase3 are detected significant increase in the contrast nephropathy model27-33.

In addition to the antioxidant effects, it has been reported in literatures that ATX has an anti-apoptotic effect34, 35. Studies have shown that the protective effects of astaxanthin against many kidney diseases is related to anti-apoptosis3, 4, 36. Considering the crucial role of oxidative stress in inducing pathological changes of IR and the antioxidant properties of ATX, ATX might alleviate tubular necrosis/ apoptosis and inflammation via scavenging free radical19. We infer that anti-apoptotic is another important mechanism that ATX moderate CI-AKI which may involve direct action of ATX (direct action on apoptotic molecules) and indirect action (mediated antioxidation). The specific mechanism that ATX moderate CI-AKI via the anti-apoptosis effects still needs further study.

ATX confers multiple renal protective effects in various experimental models of kidney diseases (Table 1).

Table 1: Animal studies investigating the nephrotoxicity effects of astaxanthin

 

Studies Animal Model Mechanism of astaxanthin
Augusti PR et al. 20081 Male Wistar rats(eight weeks-old) mercuric chloride inducedkidney function impairment anti-oxidation
Wang X et al. 20142 Male Wistar rats( eight weeks-old) trivalent inorganic arsenic-induced renal injury anti-oxidation
Guo SX et al. 20153 Adult male Sprague-Dawley rats (weighing approximately 220–250 g) severe burns induced early acute kidney injury anti-oxidation and anti-apoptosis
Qiu X et al. 20154 ?1Male ICR mice weighing 20-25 g
?2Human tubular epithelial cells (HTECs)
ischemia/reperfusion induced renal injury anti-oxidation and anti-apoptosis
Mosaad YO et al. 20165 Male albino rats (weighing 210±10 g) gentamicin-induced nephrotoxicity anti-oxidation
Kim YJ et al. 200919 Porcine proximal tubular epithelial cell line high-glucose-exposed proximal tubular epithelial cells anti-oxidation and anti-apoptosis
Ghlissi Z et al.201420 Male Wistar rats( weighing 250 ± 20 g) colistin-induced nephrotoxicity anti-oxidation
Akca G et al. 201821 Male Sprague Dawley rats (aged 3–5 months and weighing 264.83 ± 7.39 g) cisplatin-induced nephrotoxicity anti-oxidation
Okazaki Y et al. 201722 Male Wistar rats (4 weeks old) ferric nitrilotriacetate-induced renal oxidative injury anti-oxidation
Sila A et al. 201523 Male Wistar rats (~200 g) diabetic nephropathy anti-oxidation
Liu N et al. 201824 Adult male Sprague-Dawley rats (weighing approximately 160–200 g) contrast agent-induced acute kidney injury anti-oxidation and anti-apoptosis
Liu G et al. 201536 Male Balb/c mice(aged 8–10 weeks and weighing around 20–25 g) adriamycin-induced focal segmental glomerulosclerosis anti-oxidation

The protective effects of ATX are associated with its anti-oxidative and anti-apoptotic effects. ATX is a safe nutrient, with no toxic effects when it is consumed with food. Furthermore, as a natural powerful antioxidant, ATX is an excellent candidate for treating CI-AKI. The mechanism and the target of its action are still uncertain. For more in-depth understanding, more relevant animal experiments and a large number of clinical data samples are needed for confirmation, which may eventually lead to ATX becoming a novel protective agent for CI-AKI.

Conflict of interest? The authors declare that they have no competing interest.

  1. Augusti PR, Conterato GM, Somacal S, et al. Effect of astaxanthin on kidney function impairment and oxidative stress induced by mercuric chloride in rats. Food Chem Toxicol. 2008; 46: 212-219.
  2. Wang X, Zhao H, Shao Y, et al. Nephroprotective effect of astaxanthin against trivalent inorganic arsenic-induced renal injury in wistar rats. Nutr Res Pract. 2014; 8: 46-53.
  3. Guo SX, Zhou HL, Huang CL, et al. Astaxanthin attenuates early acute kidney injury following severe burns in rats by ameliorating oxidative stress and mitochondrial-related apoptosis. Mar Drugs. 2015; 13: 2105-2123.
  4. Qiu X, Fu K, Zhao X, et al. Protective effects of astaxanthin against ischemia/reperfusion induced renal injury in mice. J Transl Med. 2015; 13: 28.
  5. Mosaad YO, Gobba NA, Hussein MA. Astaxanthin; a Promising Protector Against Gentamicin-Induced Nephrotoxicity in Rats. Curr Pharm Biotechnol, 2016; 17: 1189-1197.
  6. Zuluaga M, Gueguen V, Letourneur D et al. Astaxanthin-antioxidant impact on excessive Reactive Oxygen Species generation induced by ischemia and reperfusion injury. Chem Biol Interact. 2018; 279: 145-158.
  7. Margaritis M, Sanna F, Antoniades C. Statins and oxidative stress in the cardiovascular system. Curr Pharm Des. 2017.
  8. Pisani A, Riccio E, Andreucci M, et al. Role of reactive oxygen species in pathogenesis of radiocontrast-induced nephropathy. Biomed Res Int. 2013; 2013: 868321.
  9. Yoshioka T, Fogo A, Beckman JK. Reduced activity of antioxidant enzymes underlies contrast media-induced renal injury in volume depletion. Kidney Int. 1992; 41: 1008-1015.
  10. Chang CF, Lin CC. Current concepts of contrast-induced nephropathy: a brief review. J Chin Med Assoc. 2013; 76: 673-681.
  11. Rodrigues E, Mariutti LR, Mercadante AZ. Scavenging capacity of marine carotenoids against reactive oxygen and nitrogen species in a membrane-mimicking system. Mar Drugs. 2012; 10: 1784-1798.
  12. Goto S, Kogure K, Abe K, et al. Efficient radical trapping at the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin. Biochim Biophys Acta. 2001; 1512: 251-258.
  13. McNulty HP, Byun J, Lockwood SF, et al. Differential effects of carotenoids on lipid peroxidation due to membrane interactions: X-ray diffraction analysis. Biochim Biophys Acta. 2007; 1768: 167-174.
  14. Polyakov NE, Kruppa AI, Leshina TV, et al. Carotenoids as antioxidants: spin trapping EPR and optical study. Free Radic Biol Med. 2001; 31: 43-52.
  15. Polyakov NE, Leshina TV, Konovalova TA, et al. Carotenoids as scavengers of free radicals in a Fenton reaction: antioxidants or pro-oxidants? Free Radic Biol Med. 2001; 31: 398-404.
  16. Focsan AL, Pan S, Kispert LD. Electrochemical study of astaxanthin and astaxanthin n-octanoic monoester and diester: tendency to form radicals. J Phys Chem B. 2014; 118: 2331-2339.
  17. Palozza P, Krinsky NI. Astaxanthin and canthaxanthin are potent antioxidants in a membrane model. Arch Biochem Biophys. 1992; 297: 291-295.
  18. Naguib YM. Antioxidant activities of astaxanthin and related carotenoids. J Agric Food Chem. 2000; 48: 1150-1154.
  19. Kim YJ, Kim YA, Yokozawa T. Protection against oxidative stress, inflammation, and apoptosis of high-glucose-exposed proximal tubular epithelial cells by astaxanthin. J Agric Food Chem. 2009; 57: 8793-8797.
  20. Ghlissi Z, Hakim A, Sila A, et al. Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model. Environ Toxicol Pharmacol. 2014; 37: 960-966.
  21. Akca G, Eren H, Tumkaya L, et al. The protective effect of astaxanthin against cisplatin-induced nephrotoxicity in rats. Biomed Pharmacother. 2018; 100: 575-582.
  22. Okazaki Y, Okada S, Toyokuni S. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats. J Clin Biochem Nutr. 2017; 61: 18-24.
  23. Sila A, Ghlissi Z, Kamoun Z, et al. Astaxanthin from shrimp by-products ameliorates nephropathy in diabetic rats. Eur J Nutr. 2015; 54: 301-307.
  24. Liu N, Chen J, Gao D, et al. Astaxanthin attenuates contrast agent-induced acute kidney injury in vitro and in vivo via the regulation of SIRT1/FOXO3a expression. Int Urol Nephrol. 2018.
  25. Perrin T, Descombes E, Cook S. Contrast-induced nephropathy in invasive cardiology. Swiss Med Wkly. 2012; 142: w13608.
  26. Hussien NI, Souror SM, El-Kerdasy HI, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, ameliorates contrast-induced nephropathy through suppression of oxidative stress, vascular dysfunction and apoptosis independent of glycaemia. Clin Exp Pharmacol Physiol. 2018.
  27. Quintavalle C, Brenca M, De Micco F, et al. In vivo and in vitro assessment of pathways involved in contrast media-induced renal cells apoptosis. Cell Death Dis. 2011; 2: e155.
  28. Humes HD, Hunt DA, White MD. Direct toxic effect of the radiocontrast agent diatrizoate on renal proximal tubule cells. Am J Physiol. 1987; 252: F246-255.
  29. Romano G, Briguori C, Quintavalle C, et al. Contrast agents and renal cell apoptosis. Eur Heart J. 2008; 29: 2569-2576.
  30. Kumar G, Solanki MH, Xue X, et al. Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2017; 313: F339-f350.
  31. Zhao C, Chen Z, Qi J, et al. Drp1-dependent mitophagy protects against cisplatin-induced apoptosis of renal tubular epithelial cells by improving mitochondrial function. Oncotarget. 2017; 8: 20988-21000.
  32. Wong VY, Keller PM, Nuttall ME, et al. Role of caspases in human renal proximal tubular epithelial cell apoptosis. Eur J Pharmacol. 2001; 433: 135-140.
  33. Lin X, Zhao Y, Li S. Astaxanthin attenuates glutamate-induced apoptosis via inhibition of calcium influx and endoplasmic reticulum stress. Eur J Pharmacol. 2017; 806: 43-51.
  34. Qian X, Tan C, Yang B, et al. Astaxanthin increases radiosensitivity in esophageal squamous cell carcinoma through inducing apoptosis and G2/M arrest. Dis Esophagus. 2017; 30: 1-7.
  35. Xue XL, Han XD, Li Y, et al. Astaxanthin attenuates total body irradiation-induced hematopoietic system injury in mice via inhibition of oxidative stress and apoptosis. Stem Cell Res Ther. 2017; 8: 7.
  36. Liu G, Shi Y, Peng X, et al. Astaxanthin attenuates adriamycin-induced focal segmental glomerulosclerosis. Pharmacology. 2015; 95: 193-200.
 

Article Info

Article Notes

  • Published on: May 21, 2018

Keywords

  • Astaxanthin

  • Contrast agent induced acute kidney injury
  • Anti-oxidant
  • Anti-apoptosis

*Correspondence:

Dr. Wenhua Li
Department of Cardiology, The Affiliated Hospital Of Xuzhou Medical University
Xuzhou, Jiangsu, 221002, China
Email: xzwenhua0202@163.com