Allopurinol in renal ischemia.

Journal of Investigative Surgery, 27, 304–316, 2014 C 2014 Informa Healthcare USA, Inc. Copyright ISSN: 0894-1939 print / 1521-0553 online DOI: 10.3109/08941939.2014.911395

REVIEW ARTICLE

Allopurinol in Renal Ischemia ˜ 1 Alicia Aliena-Valero,1 Beatriz Prieto-Moure,1 Anna Carabén-Redano, 1 3 Dolores Cejalvo, Alexander H. Toledo, Miguel Flores-Bellver,1 Natalia Mart´ınez-Gil,1 Luis H. Toledo-Pereyra,4 José Miguel Lloris Cars´ı1,2 1

J Invest Surg Downloaded from informahealthcare.com by University of Bristol on 11/26/14 For personal use only.

3

Experimental Surgery, Universidad Católica de Valencia, Valencia, Spain 2 Department of Surgery, University of Valencia Department of Surgery, Division of Abdominal Transplantation, University of North Carolina, Chapel Hill, North Carolina 27599, USA 4 Center for Medical Studies, Michigan State University, Kalamazoo, Michigan 49008, USA

ABSTRACT Allopurinol is a xanthine oxidase inhibitor and antioxidant free radical scavenger which facilitates the protection of ischemic organs in part via this mechanism of action. The accumulation of free radicals during ischemia and reperfusion is in great manner overcome by inhibitors of xanthine oxidase and by the development of endogenous antioxidants. The ischemic lesion generates a well-established inflammatory response with the subsequent production of inflammatory molecules characteristically present at the first stages of the injury. Inflammatory cytokines, chemokines, adhesion molecules, and other cellular and molecular compounds are consequently produced as the lesion sets in. Under these conditions, allopurinol diminishes the effect of inflammatory mediators during the ischemic inflammatory response. This study reviews the literature associated with allopurinol and renal ischemia making special emphasis on the best dose and time of administration of allopurinol regarding its protective effect. It also defines the most accepted mechanism of protection on ischemichally damaged kidneys. Keywords: allopurinol; ischemia; reperfusion; renal; free radicals; xanthine oxidase; TNF-α; NF-kB

INTRODUCTION

Over the years a large number of studies attempting to decipher the role of ALLO in ischemia and reperfusion (I/R) were subsequently published (Table 1). Although this review looks at the evolution of the use of ALLO in ischemic kidneys, emphasis was placed on the mechanism involved in preliminary studies related to the ALLO role as a builder of high-energy compounds since its role as antioxidant had not been elucidated early on. The first study related to the use of ALLO in low flow states dates back to 1969. Crowell and co-workers [7] utilized ALLO empirically in dogs under conditions of hemorrhagic shock. Two years later, De Wall and associates [8] continued these studies in order to observe the protective effect of ALLO in the ischemic myocardium. In 1972, Vasko, from De Wall’s group [9], used this drug in dogs undergoing kidney ischemia. Within a year, Toledo-Pereyra and co-workers [10] from the University of Minnesota continued the use of ALLO

Allopurinol (ALLO) was developed in 1946 by Elion, et al. at the Burroughs–Wellcome Company. It was discovered together with other molecules using spectrographic techniques when other purines were being considered for the treatment of cancer [1]. In subsequent years, it was studied as a substrate for xanthine oxidase (XO) with the purpose of inhibiting xanthine oxidation [2]. In this way, ALLO emerged in studies of new anti-cancer treatments [3] and was finally approved by the FDA in 1966 for treatment of hyperuricemia and gout [4]. XO converts ALLO to its major metabolite, oxypurinol. Both are analogues of the purine bases xanthine and hypoxanthine. They inhibit xanthine deshydrogenase (XDH) by blocking the generation of uric acid as a final catabolism product of purines and superoxide (O− 2 ) in humans [5, 6].

Received 10 February 2014; accepted 26 March 2014. ´ Address correspondence to José Miguel Lloris Cars´ı, Universidad Catolica de Valencia, C/ Quevedo 2, Valencia, 46001, Spain. E-mail: jm [email protected]

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Allopurinol in Renal Ischemia 305 TABLE 1


Year

Allopurinol in kidney ischemia-reperfusion

Model

Conclusions

1969

Dogs

Renal IR

1972

Dogs

Renal IR

1974

Dogs

Transplant IR

1974

Rats

Renal IR

1982

Rabbits

Renal IR

1985

Rats

Renal IR

1986

Rabbits

Renal IR and contralateral nephrectomy

1989

Rats

Warm renal ischemia

1992

Rats

1994

Rabbits

hypoxiareoxygenation Renal IR

1995

Rats

Renal IR

1995

Rats

Renal IR

1996

Rats

Renal IR

1998 2000

Rats Rabbits

Renal IR Normothermic renal ischemia

2000

Rats

Renal IR

2003

Rats

Renal IR

2005

Rats

Renal IR

2005 2006

Dogs Rats

Renal IR Renal IR

2007

Rats

Renal IR

2007

LLC-PK1 cells

Renal IR

2007

Dogs

Renal IR

2009

–

Renal IR

2011

Human

Renal IR

2012

Rat

Renal IR

2012

Human

Renal IR

2013

Rats

Renal IR

C

2014 Informa Healthcare USA, Inc.

Irreversibility in hemorrhagic shock is related to loss of purine base for restoration of cellular ATP. Study demonstrates a method for the prolongation of tissue and organ survival time in the face of hypoxia or anoxia by means of metabolic support. Pretreatment of donors with allopurinol and allopurinol plus hypoxanthine provides transplant kidney with partial protection from the effects of ischemia and handling. Allopurinol treatment maintains higher concentrations of ATP, ADP and AMP in kidneys during ischemia and post-ischemic recovery. Allopurinol’s action as an inhibitor of free-radical formation is another explanation of its beneficial effects in ischemia, Inhibition of xanthine oxidase with allopurinol during reperfusion improved survival rates and reduced renal dysfunction after 45 min of ischemia. Control of oxygen free radicals and protection against them by administration of scavengers and anti-oxidant compounds can be a significant supplementary tool in improving the renal function after ischemic renal surgery. The prevention of free radical-induced reperfusion injury with allopurinol (AP) and superoxide dismutase (SOD) is shown in a warm ischemia kidney model. Xanthine oxidase is likely to be the major source of oxygen free radicals during renal I/R Na+ /K+ ATPase is affected by ischemia and reperfusion and measuring its activity could be useful in predicting the results of the ischemic injury in hypoxic conditions and oxidant stress. Allopurinol administered before both ischemia and reperfusion improves the rate of renal perfusion with oxygenated blood and improves tissue oxygenation in the reperfusion phase. Allopurinol decreases renal damage following renal ischemia under enflurane anesthesia Allopurinol treatment may have beneficial effects on antioxidant defenses against ischemia-reperfusion injury of rat kidneys. Allopurinol and PGE1 attenuate renal IR injury in rats. Hyperoxic reperfusion exacerbates renal dysfunction after 30min of complete normothermic ischemia. This dysfunction may be mediated by oxygen radical-related injury. Pretreatment with allopurinol has a tendency to exert beneficial effect in histopathological changes produced by I/R. Importance of the duration in interrupted ischemia in determining the extent of renal I/R and how allopurinol counteract the oxidative stress of reperfusion. Study suggests allopurinol treatment prevented structural and functional alterations but partially prevents cortical vasoconstriction. Allopurinol pretreatment improve the I/R renal Allopurinol and Enalapril weren’t protective against I/R injury in spontaneously hypertensive rats. The production of NO by renal tissue was attenuated significantly by allopurinol. Iron chelators or anti-oxidants protect cells during the rewarming phase after normoxic but not hypoxic incubation, neither allopurinol has no effect. Hemorrheological changes were abolished with an allopurinol pretreatment. Efficacy of the allopurinol in various diseases, exploring potential uses of the allopurinol. A pretreatment with allopurinol for the elimination of pre-renal and post-renal causes of acute renal injury. Administration of allopurinol had renoprotective abilities in occluded kidney. Improvement in endothelial dysfunction in a treatment with allopurinol but the effect seems to be apart from its antioxidant effects. Allopurinol has demonstrated significant benefits by reducing reperfusion injury in rat kidneys.

References Crowell et al. [7] Vasko et al. [9]

Owens et al. [26]

Cunningham et al.[14] Hansson et al. [105] Baker et al. [25]

Hansson et al. [16]

Marx et al. [20]

Greene et al. [34] Aricioglu et al. [61] Vaughan et al. [17]

Sameshima et al. [48] Alatas et al. [18] Gupta et al. [19] Zwemer et al. [106] Rhoden et al. [107] Willgoss et al. [108] Sánchez-Lozada et al. [23] Peto et al. [109] Radovic et al. [21] Tripatara et al. [22] Bartels-Stringer et al. [110] Peto et al. [111] Suzuki et al. [6] Monedero et al. [112] Wang et al. [113] Yelken et al. [24] Keel et al. [15]

306

B. Prieto-Moure et al.

on ischemic and preserved dog kidneys that were subsequently transplanted. In this publication, we review the body of experience existent in the literature associated with the use of ALLO mainly in experimental renal ischemia. Later on, ALLO studies focused both on preservation solutions [11] and on pre-op transplant administrations [12, 13]. These papers claim beneficial effects of ALLO on various organs.

TABLE 2

Effect of dose of allopurinol in kidney I/R

Effect Positive effect


Physico-chemical Properties of Allopurinol As a hypouricaemic agent, ALLO [(1,4)-dihydropyrazol (4,3-d)-pyrimidin-7-one] is characterized by being an oxypurine base with a molecular weight of 136.11. It is minimally soluble in water and ethanol, which means it is a polar compound with a pKa of 10.2; however its mediated metabolite, oxypurinol is less soluble in water (Figure 1).

Dosage and Timing of Allopurinol Treatment for Renal Ischemia The studies shown in Table 2 have been divided into two groups: studies reporting positive effects and studies reporting negative effects, based on the survival of control groups and groups treated with different doses used in research over the years. A specific ALLO dose has not been well-defined as the “ideal” dose for I/R treatment and prevention. Positive effects have been observed with amounts ranging between 3 mg/kg, 40 mg/kg, 50 mg/kg, 100 mg/kg, and 150 mg/kg (Table 2). 100 mg/kg of ALLO has been the most commonly used dose in the studies published from Cunningham in 1974 [14] to Keel in 2013 [15]. It must be noted that Hansson in his 1986 trial [16] administered 50 mg/kg of ALLO in an experimental model in rabbits, with positive results. This was also the case with Vaughan in 1995 [17], Alatas in 1996 [18], and Gupta in 1998 [19]. Effective lower doses of ALLO (40 mg/Kg) were also reported by Marx in 1989 [20] in ischemia models with rats. This finding was later reported by Radovic in 2006 [21] and Tripatara in 2007 [22]. However, the studies conducted by SánchezLozada in 2005 [23] and Yelken in 2012 [24] had positive results with 150 mg/kg. The beneficial effect of ALLO is in great part related to the time of administration. On these times of administration, studies showed an extensive window in which the administration of ALLO might still be beneficial. The studies shown in Table 3 have been divided into two groups: studies reporting positive effects, and studies with negative effects, based on the timing of drug administration in renal I/R, in groups treated with ALLO and control groups. The reported positive effects were found from the moment ALLO was

Negative effect No effect

Dose of allopurinol

References

3 mg/kg 40 mg/kg 40 mg/kg 50 mg/kg 50 mg/kg 50 mg/kg 50 mg/kg 100 mg/kg 100 mg/kg 100 mg/kg 100 mg/kg 100 mg/kg 100 mg/kg 150 mg/L 150 mg/d 120 mg/kg 50 mg/kg 40 mg/kg

Sameshima et al. [48] Marx et al. [20] Tripatara et al. [22] Hansson et al. [16] Vaughan et al. [17] Gupta et al. [19] Alatas et al. [18] Vasko et al. [9] Cunningham et al. [14] Peto et al. [111] Wang et al. [113] Baker et al. [25] Keel et al. [15] Sánchez-Lozada et al. [23] Yelken et al. [24] Vasko et al. [9] Crowell et al. [7] Radovic et al. [21]

administered—three months before I/R on rats—[23] and also at 20 min following reperfusion [7]. In many articles reporting on ALLO administration prior to I/R, no details were given on the time of administration. Undoubtedly, this information is very important when extrapolating treatment protocols clinically. In any case, positive effects were found in I/R where ALLO was administered 30 min before ischemia [9] to 2 min after reperfusion [25].

Comparison Between Allopurinol and its Combination of Other Drugs in Renal I/R Different studies have used solely ALLO in renal I/R; however, mostly experimental trials have also taken place to determine whether better results might be obtained using ALLO in combination with other drugs. A variety of results were obtained using similar doses of ALLO, as shown in Table 4. In 1969, Crowell and associates studied the effect of ALLO and hypoxhantine at 50 mg/kg and 40 mg/kg doses respectively, positive effects being reported for the combination of both drugs only [7]. In an experimental protocol dated to 1974, Owens studied the same active principles in similar doses, finding positive effects for both the administration of ALLO alone and in combination [26]. Unlike Crowell’s study, combined ALLO and hypoxhantine were administered two days before I/R and on the experiment day [7]. In 1998, Gupta and associates explored the effect of ALLO and PGE1, obtaining good results in I/R models both for the drugs individually and in combination [19]. Radovic and his group [21] reported negative results in their 2006 study of the protective effect of ALLO and Enalapril in hypertensive rats. 40 mg/kg doses of Journal of Investigative Surgery


Allopurinol in Renal Ischemia 307

FIGURE 1 Various metabolic pathways associated allopurinol and free radical formation [2,4].

C


308


TABLE 3

Effect of timing of allopurinol in kidney I/R

Effect


Positive effect

Negative effect

Timing of administration

References

During three months before I/R Eight weeks before renal ischemia 5 hr and 1 hr before renal ischemia 30 min before ischemia 30 min before ischemia 10 min before ischemia 5 min before ischemia Immediately before renal IR Immediately before renal clamping Before ischemia Before and just after ischemia Before and just after ischemia 20 min before reperfusion 5 min before reperfusion 5 min before reperfusion 2 min before reperfusion 20 min after reperfusion 8 min before ischemia and 8 min before reperfusion 35 min after ischemia and before reperfusion 48 hr before ischemia and immediately after operated

Sánchez-Lozada et al. [23] Yelken et al. [24] Rhoden et al. [107] Vasko et al. [9] Peto et al.[111] Aricioglu et al. [61] Vaughan et al [17] Hansson et al. [16] Keel et al. [15] Peto et al. [109] Sameshima et al. [48] Gupta et al. [19] Cunningham et al. [14] Alatas et al. [18] Wang et al. [113] Baker et al. [25] Crowell et al. [7] Tripatara et al. [22] Marx et al. [20] Vasko et al. [9]

both drugs were administered right after the reperfusion process [21].

Molecular Mechanisms in Renal Ischemia and the Use of Allopurinol I/R lesions cause great cell and molecular damage resulting in impaired cellular function and viability due to necrosis and apoptosis processes. This is considered to be a cellular, vascular, and molecular injury which frequently triggers an irreversible pathological response in organs and tissues [27, 28]. Numerous scientific contributions in I/R were aimed at finding solutions to the above-mentioned complex pathology. One of the most relevant options in the 1980s was the use of ALLO as an antioxidant. However, time before, in the late 1960s, related studies were carried out using ALLO as a synthetic analogue of the TABLE 4

purine bases to modify their metabolic pathways and to interfere in nucleic acid synthesis. This was one of the first researches to study ALLO function as an XO inhibitor [29] and its protective effect on tissues with ischemic damage, persisting with other studies in the field of I/R (Table 1). What happens in renal I/R damage is the result of the activation of multiple cascades in a complex process that includes several mechanisms, causing sequential modifications in the physiopathology. Examples of this include the activation of the anaerobic pathway for glucose catabolism. This in turn causes acidosis, due to the build up of lactic acid, lysosomal instability, and mitochondrial impairment [30]; the production of oxygen free radicals that are harmful to the organ during reperfusion [31]; an increase in intracellular calcium that triggers the activation of phospholipases A and C in the cell membrane, altering cell permeability and generating vasoactive substances that transform

Comparison of the effects of allopurinol in combination with other drugs

Pharmacs Allopurinol Hypoxanthine Allopurinol + Hypoxanthine Allopurinol Allopurinol + Hypoxanthine Allopurinol PGE1 Allopurinol + PGE1 Allopurinol Enapril Allopurinol + Enapril

Dose (mg/kg) 50 mg/kg 40 mg/kg 50 mg/kg + 40 mg/kg 50 mg/kg 40 mg/kg 50 mg/kg 20 μg/kg 50 mg/kg + 20 μg/kg 40 mg/kg 40 mg/kg 40 mg/kg

Time of administration

Effect

References

20 min before ischemia 50 min after reperfusion 50 min after reperfusion

Negative Negative Positive

Crowell et al. [7]

Two days before IR and the day of the experiment

Positive

Owens et al. [26]

Just prior to clamping

After reperfusion After reperfusion After reperfusion

Positive Positive Positive Maximum protective effect Negative Negative Negative

Gupta et al. [19]

Radovic et al. [21]

Journal of Investigative Surgery



capillary dynamics and permeability [32] and, finally, causing cellular edema and other changes. All these processes start in the membrane, and it is at this point that the damage can be minimized with the use of ALLO. The membrane system triggers a variety of metabolic changes that occur during ischemia and have a cytotoxic effect on damaged tissues during reperfusion. Following the membrane effect, the ischemic lesion affects the cellular receptors of various proteins that send a series of messages into the cell and towards the nucleus to modify the cellular signaling in and out of the cell. Some alterations are XDH, complement, lipid peroxidation, and tumor necrosis factor α (TNF-α) to mention few of them [4].

Calcium Channels The calcium channel blockade protects the kidneys from damage, by playing an important role in calcium influx. Increased cytosolic calcium is associated with mitochondrial damage due to the production of free radicals in mitochondria [33, 34]. Channel blockade was tested with ALLO [35], a functional analogue that has a protective effect against renal function-related damage; and with the use of other drugs like Verapamil [36], Nisoldipine [37], and others. When ischemic damage is caused on cells, a metabolic change takes place in energy-associated compounds which result in a drop in adenosine triphosphate (ATP) and, consequently, the energy demands of cells are not met [38, 39]. This energy deficit impairs the function of Na+ /K+ ATPases in the membranes, altering the cell’s electrolytic content and producing swelling, a higher concentration of calcium in the cytosol, acidosis, and the activation of some enzymes [40]. This entails a rapid decline of ATP in the cell and the activation of phospholipases in the intracellular membrane and organelles [41, 42]. These cytosolic proteases are enzymes that act in the conversion of XDH to XO during ischemia [37] with the consequent production of free radicals. The changes described above cause the transport systems of the membrane to become dysfunctional; as an antioxidant molecule at this level, ALLO, diminishes the formation and action of free radicals. The main action of this active principle is XO inhibition and later on the generation of interference and modifications by ALLO during the synthesis of nucleic acids due to its synthetic similarity to purine base [9]. This mechanism provides sufficient energy for the membrane system to operate, diminishing intracellular Ca2+ concentration [32].

Xanthine Oxidase and the Inhibitory Role of Allopurinol The first studies on renal ischemic damage were focused on the build up of ATP on low flow and ischemic C


organs. Years later, in the 1980s, the inhibitory role of ALLO in oxygen free radicals was introduced. The free radicals were known to be noxious for most biological molecules, including proteins, polysaccharides, unsaturated lipids, and nucleic acids. They are normally formed in the purine metabolism during oxidation of hypoxanthine to xanthine, a reaction that is catalyzed by the enzyme XO [5, 43]. The body is protected against free radicals by a number of antioxidants and enzymes. During ischemia, the oxidation of hypoxanthine is interrupted, and hypoxanthine accumulates in the cells. Furthermore, throughout this phase, ATP is degraded to adenosine, inosine, xanthine, and hypoxanthine. Xanthine dehydrogenase is converted to XO by the ischemia-induced cellular calcium overload [44]. In the reoxygenation of ischemic tissue, XO pathway can form reactive oxygen species (ROS), such as superoxide (O2− ), hydrogen peroxide (H2 O2 ), and hydroxyl radical (OH− ) [45, 46]. The role of ALLO in this process is based on its action on XO, normalizing the metabolism and subsequently reducing the cytotoxic effects of various oxidation–reduction reactions involved in the evolution of renal cell damage [15]. Due to high reactivity, these free radicals have cytotoxic effects on various oxidation–reduction reactions involving different enzymes, leading to the occurrence of by-products that increase cell damage [41] (Figure 1). ALLO has been confirmed as an inhibitor of free radicals, and thus, a protector against ischemic damage [17, 47, 48]. Furthermore, the protective effect has been proven when this inhibitory compound is used in combination with other drugs (Table 4) for the treatment of renal ischemic lesion. Nonetheless, current studies on other pathways are shedding further knowledge on the molecular mechanisms, which are still being discovered.

Immune System Pathway and Effect of Allopurinol In general, the effect of ALLO on the immune system is to downregulate the cytokines and chemokines by preventing the oxidant-dependent activation that occurs in inflammation sites [49]. Since the complement system effectively identifies and eliminates harmful agents and damaged cells, its uncontrolled activation could add to tissue damage. ALLO reduces cell damage and inactivates the complement system [49]. Numerous innate immune factors have been demonstrated to contribute to renal injury after I/R, which trigger tissue inflammation and lead to further renal injury. Some alternative pathways include: complement [50], TLR-2 [51], TLR-4 [52], various cytokines and chemokines [53, 54], neutrophils, and macrophages [55, 56]. The complement system is activated in the ischemic tubular epithelial cells (TECs) and induces the

310


production of pro-inflammatory chemokines. These ischemic cells also express Toll-like receptors (TLRs) 2 and 4, which induce TECs to produce a variety of pro-inflammatory chemokines: KC, MIP-2, IL-6, TNFα, giving rise to more complement fragments and inflammation, and causing further renal injury [57].


Lipid Peroxidation and Effect of Allopurinol The peroxidation of unsaturated fatty acids by molecular oxygen may be initiated by a free radical [58]. The destruction of unsaturated fatty acids has been linked to altered membrane integrity, causing structural and functional alterations in ischemic tissues [46, 59]. Furthermore, the degradation products of lipid peroxidation could inhibit enzymes [60] like Na+ /K+ ATPase, a thiol-containing, membrane-bound enzyme that is essential for maintaining cell viability, which is extremely sensitive to lipid peroxidation. Free fatty acids may act as physiological regulators of Na+ /K+ ATPase activity, and thus have certain clinical implications [61]. Throughout this process, the ALLO function is related to protection of the Na+ /K+ ATPase activity, and therefore, provides protection against oxidative damage in the kidneys [61]. Therefore, the use of ALLO inhibits the accumulation of adenosine and its degradation by-products xanthine, hypoxanthine, and adenine nucleotides, and favors a gain in membrane phospholipids, causing the ATPase pump to operate adequately [62]. The molecular cascade of this process is associated with the NOD-like receptor 3 (NLRP3) inflammasomemediated inflammation, which has been studied recently. This mechanism uses high fructose levels to induce hyperuricemia and dyslipidaemia, causing the activation of NLRP3; the latter, associated with apoptosis-related, speck-like protein (ASC) and caspase-1, produces an overproduction of interleukins (IL-1β, IL-18, IL-6) and TNF-α. The high levels of these pro-inflammatory cytokines with janus-activated kinase 2 (JAK2) factor transduce signals activating the transcription 3 factor (STAT3). This factor activates the PAPR-α receptor, leading to the activation of the IR/IRS1/Akt/ERK1/2 system, thus producing an overexpression of SOCS3 (a cytokine suppressor), generating an increase of lipids that results in kidney damage [63]. ALLO blocks activation of this receptor, thereby decreasing lipid accumulation in kidneys and reducing renal injury [61, 63].

New Mechanistic Pathways in Renal I/R Injury Using Allopurinol Molecular studies on the protective effect of ALLO in damage caused by renal I/R focused on the impact on XO; however, more recent studies have also looked

at other molecules involved in ischemic damage, e.g., TNF-α, NF-kB, etc. We found a relationship between the inhibitory effect of ALLO in ischemic injury and the other mechanisms involved in this lesion. Our aim at this point was to verify in this revision this whole set of molecular mechanisms in order to determine the effects produced by ALLO. Now-adays, molecular studies of renal I/R focus on the role of TNF-α, a pleiotropic, proinflammatory cytokine that has multiple biological effects. TNF-α is one of the most important proinflammatory cytokines in the pathogenesis of I/R damage that affects the kidneys [64–66]; because of its multiple interactions with receptors, ROS, nitric oxide (NO), adhesion molecules, and various cytokines, chemokines, and NF-kB [66].

TNF-α Release, Receptors, and Allopurinol The role of ALLO was studied in the activation of TNFα receptors on intracellular signaling pathways of TNFα-induced mitochondrial ROS production in endothelial cells [67]. Since this cytokine acts upon endothelial cells increasing the expression of adhesion molecules and so enhances the capacity of adhesion, stimulation, and affinity with leukocytes [65], the use of ALLO inhibits chemotaxis and cytokine secretion. This event partially stops the inflammatory process, with positive effects on the damaged cell. The TNF-α release mechanism has not yet been completely elucidated after I/R. It is known that it mainly occurs in liver Kupffer cells, although it is also thought to occur in kidney cells [64]. What we know so far is that it originates in the activated mononuclear phagocytes, even though other cells such as T lymphocytes or NK cells also contribute to its production. Activating the affinity of neutrophils and monocytes with infection sources in order to activate these cells and eradicate the origin of inflammation is the main physiological function of TNF-α [64]. Their causes a variety of effects through binding of TNF receptors [68–72] 1 and 2 (TNF-R1, TNF-R2), the two main effects being: protection and stimulation of cell death [66, 73]. These receptors lack intracellular catalytic kinase domains which is the reason why they use the TNF receptor-associated death domain protein (TRADD) [65, 74] and Fas-associated death domain protein (FADD) [65, 75, 76] domains for the transduction signal. Choosing these receptors causes the transduction of the signal towards the inside of the cell to be diverted towards either protection or cell death stimulation, respectively. The importance of this molecule lies in its many interactions: receptors, ROS, NO, adhesion molecules, several cytokines, and NF-kB [66]. The action of ALLO upon them gives way to a protective effect due to the reduction of the inflammatory process caused by I/R [67]. Journal of Investigative Surgery



TNF-α, ROS, and Allopurinol During ischemic states, the mitochondria does not hold the amount of elemental oxygen needed for a full reduction of Krebs cycle intermediates and the production of cellular ATP [42]. This uncoupling of the electron transport chain causes a large production of ROS [77]. ALLO resumes ATP production, hindering the formation of oxygen free radicals through the accumulation of cytotoxic intermediaries in the cell [15]. Besides the damaging effects caused by ROS, they also trigger cytokine and chemokine release. ROS have been implicated as triggers for release of cytokines, including TNF-α in organs, such as the liver, heart, and kidneys [78, 79]. The main role of TNF-α, the subject of our renal study, based on previous research using liver and cardiac tissue, is divided into two different phases: one (early phase), based on the activation of the target cell, producing a significant augmentation of ROS, and leading to an increase of TNF-α and the complement system, which occurs after reperfusion; two (second phase or later phase), the infiltration of monocytes and neutrophils in the tissue, as the TNF-α level increases, all of which leads to an excessive kidney damage [69, 80]. Accordingly, a decrease in oxidative stress will also lower the amount of TNF-α, and at the same time, reduce kidney injury [77, 80, 81] (Figure 2).

TNF-α, NO, and Allopurinol In the ischemic process, TNF-α together with other cytokines increase NO synthesis, which is cytotoxic to the cell [82]. This effect can inhibit iron-containing enzymes that produce potent ROS peroxynitrite, which affects DNA synthesis [83]. Inhibition of NO synthesis leads to an increase in the number of neutrophils and significantly greater damage to renal tissue.

However, high NO levels stimulate apoptosis, whereas lower levels are anti-apoptotic; all of which reduce TNF-α production [84]. On the other hand, normal NO levels are essential to ensuring the supply of renal oxygen, regulating vascular tone, and acting on the vascular cells of the smooth muscle to induce vasodilatation [85]. The amount of NO is altered by ROS production, and NO is further inhibited by the effect of ALLO on XO, this reducing TNF-α levels [86]. The use of ALLO as an antioxidant strategy has proved to exert beneficial effects due to the interaction between the NO system and oxidative stress related to the elimination of the superoxide anion, thus avoiding its binding to NO and the production of cell-damaging peroxynitrites [87].

TNF-α, Cytokines, Chemokines and Allopurinol As a purine-base analogue, ALLO plays a protective role against inflammatory processes by inhibiting the release of cytokines and subsequently chemotaxis [88]. Other studies related to TNF-α have shown that its increase leads to a greater release of other molecules, e.g., IL-6, IL-8, protein-2, ENAP-78, and other chemotactic molecules, such as cytokines and cells like neutrophils. The amount of cytokines decreases as TNF-α decreases, which leads to increased activation of neutrophils, and thus, further damage in the ischemic tissue [65, 89, 90]. One of the most important interleukins in the I/R process is IL-1, a pro-inflammatory molecule that is associated to high levels of TNF-α [91, 92]. This molecule, TNF-α, plays, at least, an accessory role in I/R by increasing the production of chemokines and increasing neutrophil recruitment. As mentioned in this section, the role of ALLO would be reflected in the inhibition of XO, and therefore, in a decline in TNF-α levels and a corresponding decrease in the number of interleukins, based on

FIGURE 2 Mechanism of allopurinol protection and TNF-α (cytokines) response. C



312


FIGURE 3 Intracellular pathways mediated by TNF-α [67, 70, 73–75]..

molecular processes identified in studies on injury caused by I/R in other organs [88] (Figure 3).

TNF-α, Adhesion Molecules, and Allopurinol The results obtained so far using ALLO have been satisfactory, as all findings indicate less tissue damage as a consequence of significantly lower TNF-α levels [93]. TNF-α plays an important role in neutrophils recruitment during I/R phases. However, it is not a direct chemotactic factor for neutrophils, and therefore, it is necessary to increase the levels of interleukins and other molecules that act as intermediaries for neutrophil activation. When the activated neutrophils release proinflammatory molecules, vascular permeability is increased, causing parenchymal damage. Two important molecules in this type of renal damage are P-selectin (P, platelet) [94] and ICAM (intracellular adhesion molecule) [93], both of which are essential for neutrophil recruitment in the cells of the affected organ. Myeloperoxidase (MPO) activity is closely related to ICAM and uric acid levels. Using ALLO, uric acid levels decrease significantly, although there is increased MPO activity, which can be modified by varying the dose of ALLO [93].

TNF-α, NF-kB, and Allopurinol Ischemia leads to increase of ROS which subsequently stimulates TNF-α and NF-kB. ALLO by decreasing ROS could diminish TNF-α and NF-kB [38–40, 89]. TNF-α is an essential molecule for nuclear activation by translocation, and is involved in NF-kB, as has been shown for hepatic I/R injury. A decrease of TNF-α, and accordingly of NF-kB, generally fosters cell survival and regeneration of damaged tissue [66]. An ischemic lesion, or hypoxic or oxidative stress, increases TNF-α at the receptor level, through kinase phosphorylation [95–99]. The resulting increase in the production of NF-kB, on translocation to the nucleus, produces TNF-α transduction, which increases NF-kB levels. This occurs when TNF-R1 is activated by the TRADD domain [100]. If FADD is activated, instead of the latter domain, it will trigger an apoptosis cascade mediated by caspases 8, 9, 3, and 7, since programmed cell death occurs [101] (Figure 3). As previously mentioned, TNF-α binding to TNF-R1 can activate pathways that signal or inhibit apoptosis [66]. The mitochondrial permeability transition (MPT) is required for TNF-α stimulated apoptosis. TNF-α produces iNOS through NF-kB pathways, and thus, is thought to provide partial protection from apoptosis at low levels [102–104]. TNF-α also activates Akt, which can help prevent apoptosis by inhibiting cytochrome c Journal of Investigative Surgery

Allopurinol in Renal Ischemia 313 release after reperfusion [94]. Therefore, ALLO might prevent or attenuate the injuries produced by ischemic damage. Findings reported in studies relating to intestinal ischemia lead us to believe that the molecular mechanisms may be similar in other organs, e.g., kidneys [93] (Figure 3).

bition, and in producing direct or indirect changes in other mechanisms, such as TNF-α, IL-1, NF-kB, apoptosis, etc., in order to provide protection to damaged tissue.

ABREVIATIONS


Future Development of Allopurinol as a Protective Drug in Renal I/R ALLO has a protective effect in renal I/R. This statement is corroborated by experimental studies carried out in this field since the 1970s. The findings of these studies were based on different dosages and administration times. The most frequently used doses were 50 mg/kg and 100 mg/kg. However, there is no consensus in the studies reviewed regarding the timing of drug administration. The lack of standard criteria regarding time of administration and dosage might be a subject for further work that could contribute to underpinning studies carried out in the search for new treatment options using ALLO in renal I/R. Until now, the majority of the literature on ALLO and its role in renal I/R has focused on how to inhibit the production of free radicals in this process of inhibiting XO. More recent studies have looked at new interrelated pathways associated with ischemic damage. It would be worthwhile to continue studying the key molecular cascades (TNF-α and NF-kB) that are part of mechanisms associated with ischemic injury. Several studies have discussed the role of ALLO and these molecules in several organs (heart, liver, intestines) which coincide on their protective effect, thereby opening up the possibility of ALLO as antiTNF-α or even anti-NF-kB therapy to block the effect of either one or both of these molecules. Nonetheless, further studies focused on renal ischemia and TNF-α and NF-kB would be required to corroborate the data obtained from studies carried out in other ischemic organs. It is possible that if ALLO acts as an inhibitor of XO at the membrane level, it might also perform a similar role regarding TNF-α at membrane receptor level, in which case, it would be important to determine the impact of these membrane receptor levels on the NFkB mechanism response. Perhaps, we could find significant alternatives within already known pathways.

Akt Protein Kinase B ASC Associated Speck-Like Protein ATP Adenosine Triphosphate ENAP-78 Epithelia L Neutrophil Activating Protein78 ERK1/2 Extracellular Signal-Regulated Kinase 12 FADD Fas-Associated Death Domain Protein I/R Ischemia–Reperfusion ICAM Intercellular Adhesion Molecule IKK Inhibitor Of NF-kB Kinase IL Interleukin iNOS Inducible Nitric Oxide Synthase IR Insulin Receptor IRS1 Insulin Receptor Substrate 1 JAK2 Janus-Activated Kinase 2 KC Keratinocyte-Derived Chemokine MAPK Mitogen-Activated Protein Kinase. MIP-2 Keratinocyte-Derived Chemokine MPO Myeloperoxidase MPT Mitochondrial Permeability Transition NF-kB Nuclear Factor Kappa-B NLRP3, NOD-like receptor NO Nitric Oxide PAPR-α Peroxisome Proliferator-Activated Receptor A ROS Reactive Oxygen Species SOCS3 Suppressor Of Cytokine Signaling 3 STAT3 Transcription 3 Factor TECs Tubular Epithelial Cells TNF-R1/2 TNF Receptors 1 And 2 TNF-α Tumor Necrosis Factor TRADD TNF Receptor-Associated Death Domain Protein XDH Xanthine Deshydrogenase XO Xanthine Oxidase Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

REFERENCES CONCLUSIONS This systematic review demonstrates that ALLO has been shown to play an important protective role in renal I/R injury, and in many of the different cellular and molecular mechanisms involved in the process of ischemic injury. We can state then that ALLO has been clearly shown to play an important role in XO inhi C


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