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Saudi Journal of Kidney Diseases and Transplantation
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REVIEW ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 5  |  Page : 741-752
The protective effect of thymoquinone, an anti-oxidant and anti­-inflammatory agent, against renal injury: A review


1 Department of Medicine, Division of Nephrology, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada
2 School of Pharmacy, Pacific University, Hillsboro, OR, USA
3 Department of General Medicine, College of Medicine, Menofyia University, Menofyia, Egypt

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Date of Web Publication2-Sep-2009
 

   Abstract 

Thymoquinone (TQ), 2-Isopropyl-5-methyl-1, 4-benzoquinone, is one of the most active ingredients of Nigella Sativa seeds. TQ has a variety of beneficial properties including anti­oxidative and anti-inflammatory activities. Studies have provided original observations on the role of oxidative stress and inflammation in the development of renal diseases such as glomerulo­nephritis and drug-induced nephrotoxicity. The renoprotective effects of TQ have been demons­trated in animal models. Also, TQ has been used successfully in treating allergic diseases in humans. The aim of this review is to highlight the importance of reactive oxygen species in renal pathophysiology and the intriguing possibility for a role of TQ in the prevention of and/or protection from renal injury in humans.

How to cite this article:
Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. The protective effect of thymoquinone, an anti-oxidant and anti­-inflammatory agent, against renal injury: A review. Saudi J Kidney Dis Transpl 2009;20:741-52

How to cite this URL:
Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. The protective effect of thymoquinone, an anti-oxidant and anti­-inflammatory agent, against renal injury: A review. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2017 Nov 24];20:741-52. Available from: http://www.sjkdt.org/text.asp?2009/20/5/741/55356

   Introduction Top


Among the promising medicinal plants, Nigella Sativa (NS), is an amazing herb with a rich historical and religious background. The seeds of NS are the source of the active ingredients of this plant. Historically, the black seed has been referred to in the Islamic tradition as having healing powers. [1] It has been used in folk medicine in the Middle and Far East for many years as a traditional medicine for a wide range of illnesses including bronchial asthma, headache, dysentery, infections, obe­sity, back pain, hypertension and gastrointes­tinal problems. [2] Black seed extract, however, has been used in few clinical trials. In one of those trials, NS oil extract, administered in a dose of 40 mg/kg, significantly improved the clinical symptoms in patients with allergic di­seases such as bronchial asthma, allergic rhi­nitis and atopic eczema [3] Adverse effects did not occur, except in children receiving high doses of 80 mg/kg. It was recommended that, when used in children, it should be adminis­tered in weight-adapted doses given after meals. Its tolerability was further confirmed in ano­ther study. [4]

N. sativa seeds contain 36-38% fixed oils, pro­teins, alkaloids, saponin and 0.4-2.5% essential oil. [5] By High Performance Liquid Chromato­graphy (HPLC) analysis of NS essential oil, thymoquinone (TQ), dithymoquinone (DTQ), thymohydroquinone (THQ), and thymol (THY) are considered the main active ingredients [6] [Figure 1].

The most prominent activity of TQ is its anti­oxidant effect and therefore, an overview of the effect of reactive oxygen species (ROS) on the kidney is presented first, followed by pre­sentation of other properties of TQ.


   Reactive Oxygen Species and the Kidney Top


ROS, including super-oxide anion radical (O2 - ), hydrogen peroxide (H2O2), peroxynitrite (ONOO), hydroxyl radical (OH - ) and hypo­chlorous acid (HOCl - ) are by-products of the normal metabolic processes in the cells. The deleterious effects of oxygen are believed to result from its metabolic reduction to these highly reactive and toxic species. [7] Homology searches in human genome database resulted in the discovery of six novel NADPH oxidase enzymes. They all have, at least partially, simi­lar structure and generate ROS in response to various stimuli. High-level ROS generation at specific sites by non-phagocytic oxidases sug­gests that they have additional unique func­tions. [8] Among them, the Nox4 is believed to be most abundant in the kidney and plays se­veral roles in renal physiology and pathology. Nox4, the renal oxidase, was first described as a renal-specific oxidase and was thus origi­nally named Renox. It was shown that Nox4 is involved in angiotensin II-induced ROS pro­duction in kidney mesangial cells. [9]

ROS and Renal Physiology

ROS, nitric oxide (NO) and their interaction are important regulators of renal function. Several studies have indicated that production of both O 2 - and NO are involved in the normal kidney and vascular functions. Both may act as intermediate signaling processes involved in maintaining vascular tone and tubular func­tion. Specific roles in normal renal function for ROS, however, have now been identified. O 2 generates much of its biological effects by scavenging NO produced by the kidney. [10]

ROS and Renal Pathology

Clinical and experimental evidences of renal damage mediated by oxidative stress can be grouped under: a) glomerular, b) tubulointers- titial, and c) endothelial alterations [Figure 2].

a) Glomerular alterations

Oxidative injury may alter the structure and function of the glomerulus, mainly because of the effect of ROS on the mesangial and endo­thelial cells. [11] Oxidative stress participates in renal damage induced by hyperlipoproteine­mia. [12] Oxidation of LDL molecules by mesa­ngial cells could occur, [13] thereby activating apoptosis pathway of the endothelial and me­sangial cells, as shown by in vitro studies on these human cells, an effect prevented by anti­oxidants. [14] Lipoprotein glomerulopathy has been characterized by the development of glo­merulosclerosis and a relatively rapid progre­ssion to renal impairment. [15]

Oxidative stress could also be involved in other inflammatory glomerular lesions caused by a eries of mediators including cytokines and chemokines that lead to leukocyte acti­vation, production of ROS, and increased glo­merular damage. Various stimuli like nuclear factor- &$954;B (NF-κB) have been identified as promoters of inflammatory responses occu­rring in mesangial cells. [16]

b) Tubulointerstitial alterations

Macromolecules appear in the urinary space because of loss of glomerular permselectivity occurring in chronic renal disease. Thus, renal tubular epithelium can be exposed to injurious chemical species. Among these molecules are the oxidized LDL molecules (LDL-ox), [17] tran­sition metals, [18] hemoglobin and myoglobin, [19] or potentially nephrotoxic drugs. The exposure of tubular cells to LDL-ox may result in tubu­lointerstitial damage due to the induction of a pro-oxidant environment. [20] In turn; this oxida­tive stimulus may induce the activation of heme-oxygenase enzyme, an enzyme that catalyzes the degradation of the heme groups of hemo­globin and myoglobin, [21] two heme pigments found in the urinary space of numerous glome­rulopathies in which the glomerular barrier is impaired. Subsequently, iron liberation results in tubular production of OH - radicals and lipid peroxidation.

The accumulation of macrophages within the interstitial space of the renal cortex plays a pathogenic role in the development of tubular injury and interstitial fibrosis in progressive chronic renal diseases. [21] Proximal tubular epi­thelial cells are thought to mediate interstitial macrophage infiltration because of their ana­tomic position and ability to produce chemo­tactic cytokines, chemokines, and other infla­mmatory mediators. ROS induces gene expre­ssion of these mediators in the tubular epi­thelial cells, resulting in the recruitment of leukocytes. In renal tubular cells, the expre­ssion of chemokines, such as Monocyte Chemo­attractant Protein (MCP)-1, MCP-3, Macro­phage Inflammatory Protein-1 (MIP-1), and T cell activation gene 3, precedes the production of infiltrates containing monocytes, macro­phages, and T lymphocytes in experimental acute tubulointerstitial nephritis. [22]

c) Endothelial dysfunction

Increased ROS production has been associated with proliferation of vascular smooth muscle cells and with the pathogenesis of renal hyper­tension. [23] Numerous effects of ROS in the re­gulation of vascular functions, mainly vaso­dilation, are mediated by NO. Increased vascu­lar O 2 -production can lead to reduced amounts of bioavailable NO and impaired endothelium­dependent relaxation. [24]

Evidence for a role for ROS in various kidney diseases

Research laboratories have utilized in-vivo biomarkers to describe increased oxidative stress in uremic patients. [25] Although renal di­seases are associated with oxidative stress and reduction of NO, it is difficult to determine if this relationship is a cause or a consequence of disease. [10] Experimental models of kidney di­seases provide a good evidence to support the role of ROS in the pathogenesis of kidney disease [Table 1].

a) Glomerulonephritis (GN)

The role of oxidative stress has been con­firmed in the pathogenesis of several models of GN, either leukocyte-dependent or inde­pendent.

1) Leukocyte-dependent GN

Leukocytes can cause proteinuria (a hallmark of glomerular diseases) by damaging the Glomerular Basement Membrane (GBM). The degradation of the GBM by stimulated neu­trophils is caused by the activation of a latent metalloproteinase (MPO) enzyme by HOCl or a similar oxidant that is generated by the MPO-H2O2-halide system. [26] Anti-GBM and mesangial proliferative GN are two well-cha­racterized models of GNs in which oxidative stress has been demonstrated to induce pro­teinuria. [27] In an anti-GBM antibody model, treatment with catalase markedly reduced pro­teinuria, [28] and the use of OH- scavenger or iron chelator significantly attenuated protei­nuria. [29] In a mesangial proliferative GN model, treatment with antioxidant α-lipolic acid resul­ted in reduced generation of oxidants, and sig­nificant improvement in glomerular injury as measured histologically, and reduced expre­ssion of TGF-α1. [30]

2) Leukocyte-independent GN

The ability of glomerular cells to generate oxidants suggests that they may be important mediators of glomerular injury in glomerular diseases that lack infiltrating leukocytes. An animal model of minimal-change disease is induced by a single intravenous injection of puromycin aminonucleoside. Feeding rats a selenium-deficient diet resulted in marked diminution of GSH-Px and was accompanied by significant proteinuria, suggesting an im­portant protective role of GSH-Px in this model of glomerular disease. Similarly, inhi­bition of SOD augments puromycin-induced proteinuria. [27]

3) Ischemia/reperfusion injury

New evidence suggests that ROS have a cru­cial role in the pathogenesis of ischemia/ reperfusion injury [31],[32] and acute rejection of renal allograft. [33],[34] The mechanisms involved in renal damage and dysfunction by ROS pro­duction during ischemia/reperfusion is still incompletely understood. Immunosuppressive drugs such as cyclosporine A (CsA) induce oxidative stress in the renal allograft, through vasoconstriction mediated by NO inhibition. [35] NADPH oxidase and xanthine oxidase acti­vities were increased in experimental renal allograft, associated with increased ROS ge­neration and signs of acute rejection. [34] Inhibi­tion of xanthine oxidase with tungsten mar­kedly suppressed ROS production, inflamma­tion and signs of rejection, suggesting that it is the main source of ROS after transplantation. The ROS scavenger production correlates with also improved renal function and decreased renal tubular damage and mortality. [36] Several agents with anti-oxidant properties have been shown to be renoprotective in animal models of ischemia/ reperfusion, [37] not only by dec­reasing ROS but also through restoring the anti­oxidant enzymes.

4) Acute renal failure

Oxidative stress in patients with acute renal failure (ARF) is related to the imbalance bet­ween the production of ROS and the anti­oxidant system. Patients with severe ARF have lower plasma thiols (index of anti-oxidant capacity) and higher carbonyl levels (index of oxidative injury) than healthy subjects and pa­tients with end-stage renal disease. [38]

5) Chronic renal failure

In the rat model of chronic renal failure (CRF) with five-sixths nephrectomy, renal ex­pression of the anti-oxidant enzymes CAT and GSH-Px was reduced, suggesting that CRF suppresses the renal anti-oxidant defense sys­tem. [39] Treatment with the anti-oxidant N-ace­tylcysteine (NAC), however, improved the kidney function in this model. [40] NAC preserved GFR, lowered lipid peroxidation and renal in­flammation, decreased protein excretion and plasma aldosterone. In the late stages of CRF, NAC alone and in combination with spirono­lactone, attenuated hypertrophy of the heart and adrenals and reduced hypertension. In mice with CRF, NAC also reduced nitrotyrosine ex­pression and inhibited the progression of athe­rosclerotic lesions. [41]

6) Diabetic nephropathy

In the kidney of rats with streptozotocin­induced diabetes mellitus, either angiotensin receptor blockade or angiotensin converting enzyme inhibition prevented the development of oxidative damage in the kidney, thereby indi­cating a role of angiotensin II in renal oxi­dative stress in early diabetic nephropathy. [42] Results from several studies have shown that anti-oxidants marginally improved renal func­tion in diabetic rats [43] as well as in humans. [44],[45] The antioxidant á-lipoic acid, which previously showed promise in the treatment of diabetic neuropathy, attenuated albuminuria, glomero­sclerosis and tubulointerstitial fibrosis in long­term treatment of 16-week diabetic rats. [46] This correlated with the reduction of renal NADPH oxidase expression and activity and ROS ex­cretion.

In humans, it was reported that higher levels of 8-OH-G, a marker of oxidative damage to DNA, were found in type-1 and type-2 dia­betic patients, patients with diabetic compli­cations, patients with diabetic nephropathy and albuminuria. [27]

7) Drug-induced nephropathy

The generation of free oxygen radicals is one of the possible mechanisms by which several drugs exert their nephrotoxic effects. It was suggested that oxidative stress might underlie in the pathogenesis of vancomycin (VCM)­induced nephrotoxicity. Nephrotoxicity due to VCM might be caused by indirect generation of ROS associated with inflammatory events in vivo. [47] ROS have been also proposed as the causative agents of cell death in various mo­dels of toxic renal failure including cisplatin, [48] aminoglycosides [49] and doxorubicin (DOX)­induced nephropathy. [50] The involvement of ROS has also been documented in the etiology of ifosfamide (IFO)-induced Fanconi syndrome. Ifosfamide has been reported to cause renal GSH depletion and lipid peroxide accumu­lation. [51]




   The Pharmacological Properties of TQ Top


Several studies have been conducted, parti­cularly during the past two decades, on the effects of N. sativa seed extract or its active compound TQ on various body systems in vivo or in vitro . [5],[52]These pharmacological effects are shown in [Table 2]. Among these effects, the anti-oxidant and the anti-inflammatory proper­ties are here in reviewed.

Anti-oxidant properties

More than 35 studies have addressed the in vivo and in vitro antitoxic properties of TQ. [52] TQ and a synthetic structurally-related tert­butylhydroquinone, efficiently inhibited iron­dependent microsomal lipid peroxidation in vitro in a concentration-dependent manner. [53] Stimulation of polymorphonuclear leukocytes with TQ showed protective action against the damaging effects of O 2-, generated either photo­chemically or biochemically, indicating its po­tent O - scavenger activity. [54]

Prophylactic treatment of mice with TQ, one hour before carbontetrachloride (CCl4) injec­tion, ameliorated hepatotoxicity of CCl4 as evi­denced by the significant reduction of the ele­vated levels of serum liver enzymes, and sig­nificant increase of the hepatic GSH content. [55] Also, TQ prevented the ischemia/reperfusion­induced alterations in gastric mucosal GSH and Super Oxide Dismutase (SOD) in rats. [56]

Anti-inflammatory properties

Progression and persistence of acute or chronic state of inflammation is mediated by a number of mediators including eicosanoids, oxidants, cytokines, and lytic enzymes secre­ted by the inflammatory cells, macrophages and neutrophils. [57] Inflammation is also me­diated by two main enzymes, cyclooxygenase (COX) and lipoxygenase (LO). [58] COX gene­rates prostaglandins (PGEs) and thromboxane from arachidonic acid, while LO catalyzes the formation of leukotriens (LTs). Therefore, both PGEs and LTs function as the main mediators of allergy and inflammation. [59] TQ inhibited both COX and LO pathways of arachidonate metabolism in rat peritoneal leukocytes sti­mulated with calcium ionophore A23187, as shown by dose-dependent inhibition of throm­boxane B2 and LTs levels. Thus, inhibition of both COX and LO pathways is a key factor mediating the anti-inflammatory effects of TQ. [60]

The use of TQ has also been shown to have anti-inflammatory effects in several inflamma­tory diseases, including experimental allergic encephalomyelitis (EAE), [61] colitis, [62] and arth­ritis. [63]


   The Experimental Use of TQ in Animal Models of Kidney Diseases Top


Badary and co-workers investigated the effect of TQ on the nephropathy and oxidative stress induced by DOX in rats. It significantly lo­wered serum urea, triglycerides, and total cho­lesterol. Similarly, triglycerides, total choles­terol and lipid peroxides in the kidneys of TQ­treated rats were decreased significantly com­pared with DOX alone. It was concluded that TQ suppressed DOX-induced nephrosis. [64]

Oral supplementation of TQ in drinking wa­ter rendered rats significantly less susceptible to IFO-induced renal abnormalities. Also, IFO­induced glucosuria, phosphaturia and Gluta­thione S-Transferase (GST) enzymuria were significantly less pronounced in rats that re­ceived TQ. [51] Additionally, TQ supplementation in drinking water resulted in a complete rever­sal of gentamicin-induced increase in blood urea, creatinine and lipid peroxides. In addition, it decreased GSH, ATP, GSH-Px and catalase enzymes to the control values. Moreover, his­topathological examination of kidney tissues confirmed the biochemical data, where-in TQ supplementation prevented gentamicin-induced degenerative changes in kidney tissues. [65]


   Anti-oxidant Agents in Drug-induced Nephropathy Top


Based on the previously reported evidence of the role of ROS in different forms of kidney diseases, the role of anti-oxidant agents was studied in different conditions. Several animal models have been used to study the possible role of anti-oxidants of natural origin in atte­nuating drug-induced nephropathy.

Omega-3 fatty acids favorably modified chronic CsA nephrotoxicity in Sprague Dawley rats. [66] Omega-3 at a dose of 100 mg/kg/day was co-administered with CsA (100 mg/kg/ day) for 80 days. CsA is known to induce tubular atrophy, interstitial fibrosis, and chro­nic inflammatory cell infiltration. Treatment with Omega-3, significantly improved tubular atrophy and interstitial fibrosis but not chronic inflammatory cell infiltration.

Anti-oxidant foods like garlic and black grape, [67],[68] were also studied in CsA nephro­toxicity. [69] CsA increased Malondialdehyde (MDA) levels and decreased Catalase enzyme activity in the kidneys of Sprague Dawley rats. These effects were reversed by oral admi­nistration of aqueous garlic and black grape extracts. They also decreased the glomerular sclerosis, vascular congestion, focal tubular necrosis and thyroidation induced by CsA.

Cisplatin is an extensively used synthetic anticancer drug, which is known for its oxida­tive stress-mediated severe nephrotoxicity. [70] Several anti-oxidants, including TQ, have been experimentally used to minimize its nephroto­xicity. [Table 3] shows the comparison of the clinical effects of TQ with some of the other known anti-oxidant agents such as Vita-mins E and C, Selenium, Curcumin and Lyco-pene, a naturally occurring carotenoid. A single injec­tion of cisplatin was used to induce nephroto­xicity in different animal models. Treatment with anti-oxidants, either pre, post, or both, were used to alleviate cispalatin-induced neph­rotoxicity. [Table 3] shows that TQ achieved the best clinical effects manifested in this animal model of drug-induced nephroto-xicity. It in­duced the highest percentage of reduction in urea and creatinine and increase in creatinine clearance, compared to cisplatin only group as well as with the use of different anti-oxidants.


   Conclusion Top


TQ is the main active ingredient of N. sativa seeds, one of the most promising medicinal plants with many therapeutic effects. One of its most important effects is its anti-oxidant activity. It acts as an anion scavenger that neu­tralizes oxygen radicals. Several studies have proved the usefulness of TQ in ameliorating the nephrotoxicity induced by drugs that exert their adverse effects through generation of ROS. Also, none of the studies reported that the use of TQ in moderate doses had appre­ciable toxic effects. These results should raise the intriguing possibility that TQ may have a beneficial adjunctive effect similar to Flax seed and 3-Omega fatty acids. As such, effi­cacy of TQ to retard progression in chronic kidney diseases should be tested in patients with acute and chronic renal diseases.[90]

 
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