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Cardiovascular Research 2005 67(4):594-603; doi:10.1016/j.cardiores.2005.05.005
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Copyright © 2005, European Society of Cardiology

Cellular and molecular mechanisms of sex differences in renal ischemia–reperfusion injury

Ajay Khera,c, Kirstan K. Meldruma, Meijing Wanga,c, Ben M. Tsaia, Jeffrey M. Pitchera and Daniel R. Meldruma,b,c,*

aDepartments of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States
bCellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
cIndiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States

* Corresponding author. 545 Barnhill Drive, Emerson Hall 215, Indianapolis, Indiana 46202, United States. Tel.: +1 317 313 5217; fax: +1 317 274 2940. Email address: dmeldrum{at}iupui.edu

Received 7 March 2005; revised 21 April 2005; accepted 3 May 2005


   Abstract
Top
 Abstract
1. Introduction
 2. Renal ischemia reperfusion...
 3. Mechanisms of gender...
 4. Summary
 Acknowledgments
 References
 
Renal ischemia–reperfusion (I/R) is an important etiopathological mechanism of acute renal failure (ARF). Despite improvements in the treatment of ARF, it is associated with significant morbidity and mortality. I/R injury also occurs during renal transplantation and leads to reduced allograft survival. Sex differences have been found in I/R injury in many different organs including the kidney. Women have half the mortality of men in ARF. In animal models also, females are protected against renal I/R injury. The mechanisms by which sex affects the outcome to renal I/R injury are being actively investigated. This review will examine the evidence for gender differences in renal I/R injury and discuss the probable mechanisms by which sex affects the renal response to I/R injury.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Renal ischemia reperfusion...
 3. Mechanisms of gender...
 4. Summary
 Acknowledgments
 References
 
Acute renal failure (ARF) caused by renal ischemia/reperfusion (I/R) is an important clinical problem. Even though great progress has been made in patient care, there is still high morbidity and mortality associated with ARF. Renal I/R injury is also an important determinant of allograft survival after transplantation [1]. Studies have shown that early I/R injury can lead to the initiation of inflammatory cascade, which may result in delayed graft function and decreased long term renal allograft survival [1,2]. Blocking the initial inflammation prevents this loss of function [3–9]. This is similar to the important role of inflammation in myocardial I/R [10,11]. In the myocardium, sex differences exist in the inflammatory response and the outcome after I/R [12–15] suggesting that the same may be true for renal I/R.

In addition, sex differences exist in different renal diseases. Studies suggest that progression of renal disease is faster in men. A meta-analysis by Neugarten et al. [16] showed that males had a rapid rate of progression of renal disease in membranous nephropathy, IgA nephropathy and autosomal dominant polycystic kidney disease and had worse outcome in chronic renal disease. As this study did not look at the baseline differences between genders, questions have been raised about whether gender is an independent factor in these differences or that men had greater risk factors, which led to this disparity. Furthermore, a study evaluating the efficacy of angiotensin-converting enzyme inhibitors on the progression of renal disease found that after adjusting for baseline variables females had faster progression instead of slower [17]. However, the mean age of the patients was 52 years and hence the majority of women may have been postmenopausal. The Modification of Diet in Renal Disease (MDRD) study showed that females, especially <52 years, had a slower rate of progression [18]. However, after adjusting for proteinuria, blood pressure and HDL cholesterol the gender differences were no longer significant. In contrast, studies looking at outcomes in ARF patients have shown that men have twice the mortality of women and have found that gender is an independent predictor of mortality in ARF [19–21].

Consistent with the clinical studies in ARF, animal studies have also shown females to be protected against renal I/R injury. A study by Park et al. [22] showed that males had deterioration of kidney function after bilateral renal ischemia of 30 min while females were relatively protected and developed dysfunction only after 60 min of ischemia. They also showed males to have a higher mortality rate. Similarly, Muller et al. [23] reported that 8% males compared with 75% females survived seven days after ischemia. In another study, Fekete et al. [24] showed that females have lower blood urea nitrogen, serum creatinine and less severe tubular necrosis after renal I/R compared to males. These studies show that sex differences in renal I/R injury exist.

This review will provide a brief overview of the pathophysiology of renal I/R injury followed by a discussion of the possible mechanisms of sex differences in renal I/R. For greater detail on renal I/R injury, the reader may refer to some excellent reviews that have recently covered different aspects of the pathogenesis of ischemic ARF [25–33].


   2. Renal ischemia reperfusion injury
Top
 Abstract
 1. Introduction
 2. Renal ischemia reperfusion...
3. Mechanisms of gender...
 4. Summary
 Acknowledgments
 References
 
Renal I/R injury occurs through a complex interaction between renal hemodynamics, inflammatory mediators, endothelial and tubular injury. The kidney receives 25% of the cardiac output but the majority goes to the cortex and hence even slight changes in perfusion may lead to ischemia of the medulla. The S3 segment of the proximal tubule in the outer strip of the outer medulla is the most susceptible to I/R injury [34]. Differences between these cells and other cells in the medulla are being investigated to identify reasons for their increased susceptibility [35].

During I/R injury renal endothelial and parenchymal cells secrete proinflammatory cytokines (TNF, IL-1, IL-6, etc), chemokines (MCP, IL-8, etc) and activate complement [25]. The cytokines and the reactive oxygen species (ROS) produced by I/R injury upregulate the expression of adhesion molecules like ICAM, VCAM and P selectin [27]. The combination of chemokines, cytokines and adhesion molecules leads to recruitment, activation and sequestration of leukocytes, which generates further ROS and cytokines and potentiates the injury (Fig. 1A and B).


Figure 1
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  		Fig. 1 Schematic illustration of the renal inflammatory response after ischemia–reperfusion. (A) Pre-ischemic kidney with sodium–potassium ATPase (Na+/K+ ATPase) localized to the basolateral membrane. (B) Post ischemia/reperfusion kidney with disruption of actin cytoskeleton and loss of polarity in epithelial cells causing apical localization of Na+/K+ ATPase. The injured epithelial and endothelial cells also secrete inflammatory cytokines which upregulate adhesion molecules. Leukocytes are recruited and activated by the adhesion molecules and inflammatory mediators present. The activated leukocytes also generate inflammatory cytokines thus further increasing the injury.

 
Endothelial dysfunction is an important component of initiating and continuing renal tubular epithelial injury and contributes to the pathogenesis of ischemic ARF [28]. Endothelial injury may aggravate the inflammatory response through loss of normal nitric oxide (NO) production due to inhibition of endothelial nitric oxide synthase (eNOS). NO reduces leukocyte-induced injury by blocking leukocyte sequestration and activation. However, I/R also increases inducible nitric oxide synthase (iNOS), which potentiates injury [36,37] as the nitric oxide produced reacts with oxygen radicals to form peroxynitrite [38]. Also, the high output production by iNOS might suppress eNOS [39]. This imbalance between the two NOS may be an important component of renal I/R injury.

Due to I/R injury, there is disruption of the actin cytoskeleton, loss of tight junctions and adherens junctions in the proximal tubular epithelium. This causes a change in the localization of polarized membrane proteins, especially sodium–potassium ATPase (NKA) (Fig. 1A and B). NKA is normally localized to the basolateral plasma membrane but after ischemia appears on the apical plasma membrane [40]. This reduces the efficiency of transcellular Na+ transport and increases Na+ delivery to the distal tubules leading to glomerular vasoconstriction and decreased GFR through tubuloglomerular feedback [25]. In addition, I/R causes decreased NKA activity, due to ATP depletion, leading to increased intracellular Na+ concentration, which increases intracellular Ca2+ and causes increased injury.

I/R injury causes cell death by both necrosis and apoptosis. Recently it has been shown that smaller insults lead to apoptosis while larger insults lead to necrosis. Our group has shown that TNF is involved in apoptosis after renal I/R and that p38 mitogen activated protein kinase (MAPK) and nuclear factor kappa B are crucial for TNF production and TNF mediated apoptosis [3,5,6,8,9]. Two pathways of apoptosis have been clearly delineated each of which leads to activation of the downstream effector caspase-3. One is receptor dependent and initiated by activation through death domains (TNF receptor associated and Fas associated), which activate caspase-8 followed by caspase-3. The other pathway is through mitochondrial release of cytochrome c, which activates caspase-9 and then caspase-3. The cells have many molecules that regulate these apoptotic pathways. Important among them are phosphatidylinositol 3 kinase (PI3K)/Akt and members of the Bcl-2 family.


   3. Mechanisms of gender differences in renal response to I/R injury
Top
 Abstract
 1. Introduction
 2. Renal ischemia reperfusion...
 3. Mechanisms of gender...
4. Summary
 Acknowledgments
 References
 
In comparison to myocardial I/R, gender differences in renal I/R have not been that extensively studied. Certain mechanisms for these sex differences in renal I/R have been proposed but the exact mechanism remains to be determined. However, it is a field of study under active investigation and the rest of the review will focus on the possible mechanisms.

Sex differences likely exist at several levels, but the primary factor may be sex hormones. In renal I/R, Muller et al. [23] have reported that castration and sexual immaturity did not affect the I/R injury produced in females but decreased the injury produced in males suggesting that testosterone may play a bigger role in these gender differences than estrogen. Park et al. [22] showed similar results with castration of males and females, in addition they showed that testosterone administration increased renal I/R injury in females, ovariectomized females and castrated males while administration of estrogen provided protection to males. Thus these studies suggest that testosterone or the ratio of testosterone/estrogen may be the important determinant of these sex differences in renal I/R injury.

Studies are currently investigating the molecular mechanisms of these gender differences. The cellular mechanisms and signaling pathways that have been implicated in these sex differences are discussed below.

3.1. Mitogen activated protein kinases
Mitogen activated protein kinase (MAPK) is a family of Ser/Thr protein kinases that regulate many cellular processes. They are activated by upstream kinases referred to as MAP kinase kinase (MAPKK or MEK) which themselves are activated by MAP kinase kinase kinases (MAPKKK or MEKK). This sequence of phosphorylation causes amplification of the signal. The MAPK family is divided into 3 subfamilies: extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. These MAPKs are activated by I/R injury not only in the kidney but also other organs. ERK promotes cell survival while JNK and p38 lead to cell death. Some studies postulate that it may be the balance between the two (ERK versus JNK/p38) that determines the fate of the cell [41]. Renal I/R causes necrosis predominantly of the proximal tubules (PT), especially the S3 portion [34], while the thick ascending limb (TAL), distal convoluted tubules and collecting ducts are relatively spared. There is increased ERK phosphorylation in TAL but not in PT cells while JNK is activated in both these cells [35]. Hence it has been speculated that this difference in the response may be the cause for the relative difference in the survival of these cells. Other studies have also shown that renal I/R induces JNK [42]and inhibition of JNK decreases the development of ARF [43], which is consistent with other studies showing that JNK promotes cell death [44,45]. In addition, ERK inhibition decreased survival in TAL cells while ERK activation increased it in PT cells [35]. Studies on renal ischemic preconditioning [46] and transient ureteric obstruction [47] have shown that previous ischemia or ureteric obstruction provides protection against subsequent ischemic injury. These studies have shown that these interventions decrease the production of JNK and p38 caused by the ischemic insult while I/R induced production of ERK is not affected. Hence, providing further evidence that it maybe the balance between ERK and JNK/p38 which is the determinant of I/R injury. Similar results have also been found with chemical preconditioning using cyclosporine and FK506 [48].

Park et al. [22] found that JNK is activated with ischemia but more so in males than females. Castration reduced JNK activation in males but did not alter it in females. This suggests that testosterone may play a more important role in JNK activation. In support, they found that testosterone administration to females increased JNK activation. However, estrogen administration to males lowered JNK activation (Table 1). They also found that I/R increases ERK phosphorylation and it is higher in females than in males. Ovariectomy reduced ERK activation while castration did not alter it, suggesting that estrogen may be more important in mediating sex differences in ERK activation. Neudling et al. [49] have shown that in cardiomyocytes 17 beta estradiol caused a rapid and transient ERK activation while it caused a rapid and sustained rise in JNK phosphorylation. These rapid effects of estrogen are thought to occur through the nongenomic action of sex steroids. Kousteni et al. [50] have described these nongenomic actions in the bone. They showed that estrogen through the estrogen receptor activated the Src/Shc/ERK pathway and mediated the antiapoptotic effect of estrogen (Fig. 2A). Interestingly, they also showed that this effect could be mediated by estrogen or androgen receptors irrespective of whether the ligand is estrogen or androgen. Migliaccio et al. [51] have found similar findings in other cell lines. The role of these pathways in I/R injury and in mediating the gender differences still needs to be defined.


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  		Table 1 Effects of estrogen and testosterone on mechanisms involved in I/R injury

 

Figure 2
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  		Fig. 2 Possible mechanisms by which estrogen provides protection from renal ischemia/reperfusion (I/R) injury. Plain lines indicate activation or increase while dashed/interrupted lines indicate inhibition or decrease (–). (A) Estrogen acts through estrogen receptor (ER) to activate Src and phophatidylinositol 3-kinase (PI3K). (B) Src activates extracellular regulated kinase (ERK), which increases endothelial nitric oxide synthase (eNOS) and is anti-apoptotic. (C) PI3K activates Akt, which is anti-apoptotic, and increases eNOS that leads to increased nitric oxide (NO) production. (D) NO protects by causing vasodilation directly and by decreasing endothelin production. (E) Estrogen also acts as an antioxidant to decrease the oxidative stress and hence maintains sodium–potassium ATPase (NKA) activity preventing the I/R induced increase in intracellular sodium ([Na+]) concentration. The increased [Na+] concentration leads to increased intracellular calcium ([Ca2+]), which produces cellular injury.

 
Our group has shown sex differences in p38 MAPK production in myocardial I/R injury [15]. We found that females had lower p38 MAPK activation after myocardial I/R and this was associated with lower proinflammatory cytokine production and better recovery of myocardial function. In addition, we have shown that testosterone increases the p38 MAPK activation produced by I/R [14]. Similarly, Angele et al. [52] have shown that testosterone is responsible for the increased p38 MAPK activation in male macrophages after trauma-hemorrhage. As p38 MAPK mediates I/R induced TNF production and TNF induced apoptosis, therefore, sex differences in p38 MAPK may be responsible for the gender differences noted in renal I/R.

These studies show that there are sex differences in MAPK activation after I/R and they may mediate the gender differences in renal I/R injury. However, more studies are needed to further delineate the involvement of these pathways.

3.2. Nitric oxide
Nitric oxide (NO) plays an important role in renal vascular tone and hemodynamics [53,54]. NO is produced from L-arginine by nitric oxide synthase (NOS). There are 3 NOS: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Of these, nNOS and eNOS are calcium dependent (cNOS) while iNOS is calcium independent (ciNOS). The beneficial effect of NO in renal I/R injury has been shown by the protective effect of NO donors [55–57]. Sex differences in NO have been shown in the kidney in different animal models [58–60]. Females have higher eNOS mRNA and protein expression compared to males [61,62]. Also, ovariectomy reduced eNOS while estrogen replacement increased it.

Park et al. [22] showed that after renal I/R ciNOS activity increased in both males and females while cNOS activity decreased in males but increased in females. This difference in cNOS activity may be an important component of the gender difference noted. They also showed that testosterone decreased the cNOS activity post I/R while estrogen increased it. Similarly, many studies in other organs have also shown that estrogen and testosterone modulate NOS expression and NO production [49,63–66]. Estrogen activates eNOS in a biphasic manner [67]. The initial increase is mediated by ERK [49,68] while the latter occurs through phophatidylinositol 3-kinase (PI3K) [67] (Fig. 2B and C). Both these pathways are activated through the rapid, nongenomic actions of estrogen. ERK is probably activated through the Src/Shc/ERK pathway while estrogen receptor alpha interacts with a subunit of PI3K and stimulates it leading to activation of both eNOS and Akt. Thus, estrogen may mediate the gender differences in renal I/R through differences in NOS expression and NO production.

3.3. Sodium–potassium ATPase
Elevated intracellular calcium causes cellular injury during renal I/R [69]. An increase in intracellular Na+ concentration correlates with the increased Ca2+. Accumulation of Na+ is caused by inhibition of sodium–potassium ATPase (NKA) activity, which occurs due to decreased ATP production. The increased Na+ leads to Na+/Ca2+ exchange by sodium–calcium exchanger (NCX) and hence Ca2+ overload (Fig. 2E). Sex differences in renal NKA have been shown by Fekete et al. [24]. They found that the mRNA expression of NKA {alpha}1 subunit was higher in females and this difference was further increased after I/R. I/R lead to a decrease in mRNA expression of NKA {alpha}1 subunit in both genders but it was more severe in males. However, protein levels of NKA {alpha}1 and NKA activity were similar between genders in the control groups but after I/R males had a greater decrease in both. In addition, estradiol has been shown to stimulate NKA in the myocardium and antagonizes the depression in NKA caused by ischemia [70]. This suggests that differences in NKA activity might mediate sex differences in renal I/R injury.

Further support for the role of NKA in mediating sex differences is provided by studies on NCX in the heart. NCX countertransports three Na+ ions for one Ca2+ ion. NCX can function in either direction depending on the transmembrane gradients of the ions and the membrane potential. NCX normally works in the calcium removal mode but in ischemia there is an increase in intracellular Na+ and change in the membrane potential, which leads to reversing of the NCX [71]. Isolated hearts of transgenic mice overexpressing NCX had greater I/R injury than wild type mice [72]. However, female transgenic mice were relatively protected from the increased I/R injury compared to male transgenics. Sugishita et al. [73] studied myocytes isolated from NCX overexpressing mice and found lower intracellular calcium after metabolic inhibition in females. Females had lower intracellular sodium suggesting that the decreased calcium in females might be due to this. Due to the stoichiometry of NCX, exchanges 3 sodium ions for 1 calcium ion, even small differences in intracellular sodium would lead to larger differences in calcium. Interestingly, they also found that estrogen could reduce the increase in intracellular sodium and calcium produced by metabolic inhibition. In another study, Sugishita et al. [74] showed that tamoxifen did not block the estrogen mediated inhibition of the rise in Ca2+. Also estrone, estriol, alpha and beta estrogen produced the same results while testosterone did not, suggesting that these effects might be mediated by antioxidant mechanisms due to the hydroxyl group at the C3 position of the A ring of the steroid molecule. Oubain (NKA inhibitor) and KB-R7943 (NCX inhibitor) blocked these protective effects. This suggests that the antioxidant effect helps maintain NKA function and this decreases Na+ accumulation, which leads to decreased Ca2+ entry through NCX and hence decreased injury (Fig. 2E).

Similar to the role of NCX in myocardial I/R injury, studies with NCX inhibitors have shown that NCX plays an important role in renal I/R injury [75,76]. In addition, heterozygous knockouts of NCX were relatively protected against renal I/R injury [77,78]. Thus, estrogen might through its antioxidant effects maintain NKA function, mediate differences in intracellular sodium and calcium concentrations and finally protect against renal I/R injury.

3.4. Endothelin
Endothelin (ET)-1, a potent vasoconstrictor, is elevated in the plasma in patients with ARF and in the kidney in animal models of ischemia induced ARF [79–81]. This increase occurs especially in the peritubular capillaries and may be responsible for tubular necrosis [80]. Administration of ET-1 antibodies or ET A receptor antagonists but not ET B receptor antagonists decreased the renal dysfunction produced by I/R [81–85].

Muller et al. [23] showed gender differences in recovery from renal I/R injury and that these differences were abolished by administration of LU 135252 (a selective ETA receptor antagonist) suggesting that ET might mediate the gender differences in renal I/R injury. Estrogen has been shown to decrease ET-1 production [86–88]. Takaoka et al. [89] studied male rats with estrogen administration and they found that estrogen dose dependently reduced renal injury and dysfunction and also decreased the ET-1 overproduction caused by I/R injury. However, the mechanism by which estrogen reduces endothelin production is not defined.

The possible mechanisms may include estrogen increasing NO which downregulates endothelin or that estrogen decreases Ca2+ overload and hence decreases the endothelin production. Different NO donors have shown that increased NO inhibits the increased endothelin-1 production caused by I/R [90,91] (Fig. 2D). Jeong et al. [91] showed that sodium nitroprusside (a NO donor) given before renal ischemia decreased endothelin production and provided protection from I/R. In addition, decreased ET-1 production has been observed in studies using NCX inhibitors and in mice heterozygous for NCX undergoing renal I/R [75,76,78]. This suggests that intracellular Ca2+ overload leads to increased ET-1 production. In support, studies have shown that increase in intracellular Ca2+ through reverse NCX does occur in vascular endothelial cells [92] and that increased Ca2+ does induce expression of ET-1 [93].

3.5. Adenosine and ATP sensitive potassium channels
During hypoxia, ischemia or inflammation adenosine is produced locally and mediates a variety of functions. These heterogeneous effects are mediated through multiple adenosine receptors localized in different regions of the kidney. Four G protein-coupled receptors have been identified: A1, A2A, A2B, and A3. A1 and possibly A3 receptor activation produce preconditioning and provide protection, possibly by increasing mitochondrial ATP sensitive potassium (KATP) channel activity [94,95]. A2A agonists also provide protection from I/R injury, which is correlated with an inhibition of neutrophil oxidase activity, neutrophil accumulation, endothelial adhesion molecule expression and cytokine production [96]. A2A receptor also mediates the vasodilation produced by adenosine and increases renal blood flow and glomerular filtration rate. In renal ischemia, A1 and A2A receptor activation is protective [96,97].

Estrogen has been shown to decrease infarct size in cardiac I/R through mitochondrial KATP channels [98]. Estrogen has also been used in coronary angioplasty patients and reduced myocardial ischemia caused by balloon inflation, possibly through KATP channels [99]. The opening of these channels results in potassium influx, which decreases the driving force for calcium uptake and decreases calcium induced injury. Similar to its role in cardiac I/R, KATP channels are protective in renal I/R injury. Diazoxide (a KATP channel opener) provided protection in renal I/R [100]. These results suggest that estrogen may activate KATP channels and provide protection from renal I/R through it.

In contrast, testosterone has been shown to block adenosine mediated vasodilation [101]. However, Er et al. [102] have demonstrated in a cellular model that testosterone decreased ischemia-induced death of cardiomyocytes by activating KATP channels. Thus, further research is needed to clarify the effect of testosterone on adenosine and KATP channels and the role of these mechanisms in renal I/R.

3.6. Apoptosis
I/R injury can lead to cell death by necrosis or apoptosis. Prolonged renal ischemia leads to necrotic cell death while in shorter periods of renal ischemia apoptosis is the primary mode of cell death [103]. Inhibiting renal apoptosis protects against renal I/R injury [30,104]. Testosterone has been shown to promote apoptosis in vascular endothelial cells and renal tubular cells [105,106]. Verzola et al. [106] showed a dose dependent effect of testosterone on apoptosis in renal tubular cells after serum deprivation. They also showed that testosterone upregulated Fas, Fas ligand and Fas associated death domain. Testosterone also decreased Bcl-2 while increasing Bax expression. The use of caspase-3 inhibitor, caspase-8 inhibitor or caspase-9 inhibitor reduced the apoptosis produced by testosterone. These studies indicate the possible role of testosterone in promoting apoptosis though further research is needed to delineate the mechanism of this effect.

Studies suggest that one of the critical regulators of cell survival is Akt (protein kinase B) [107–109]. Akt is activated by many different stimuli primarily through phophatidylinositol 3-kinase (PI3K) (Fig. 2C). Akt is present in the cytoplasm but after phosphorylation (activation) it translocates to the nucleus and phosphorylates its targets. One such substrate is forkhead [110], which is proapoptotic in the dephosphorylated state and is translocated from the nucleus to the cytoplasm on phosphorylation. Activation of Akt and phosphorylation of forkhead proteins has been shown after renal I/R injury and in LLC-PK1 cells undergoing chemical anoxia [111]. Other potential mechanisms for the antiapoptotic effect of Akt include phosphorylation of caspase 9 and phosphorylation of Bcl-XL/Bcl-2 associated death promoter (BAD) [109,112]. Sex differences have been found in Akt in different organs including the kidney. Park et al. [22] found that female kidneys have higher basal levels of Akt than males. Castration and estrogen supplementation of males led to an increase in basal Akt while ovariectomy and testosterone supplementation of females reduced basal Akt. Ischemia led to an increase in Akt but this was transient in the non-protected groups. Similar to basal Akt levels, sustained Akt activation after ischemia was produced with estrogen and decreased by testosterone. Similarly, Camper-Kirby et al. [113] observed gender differences in Akt in cardiomyocytes. They found that women had higher nuclear localization of phospho-Akt in the myocardium. They also observed that estradiol administration increased the nuclear localization of phopho-Akt in neonatal cultured cardiomyocytes. In addition, Patten et al. [114] showed that 17 beta estradiol administration to ovariectomized female increased Akt activation and reduced apoptosis after in vivo coronary artery ligation. In an in vitro model they showed that the antiapoptotic effect of estradiol was mediated through the estrogen receptor and PI3K-Akt mediated pathway. Simoncini et al. [67] have further clarified the mechanism of Akt activation by estrogen. They showed that estrogen receptor alpha interacts with a subunit of PI3K (nongenomic action) and stimulates it leading to activation of Akt and eNOS (Fig. 2C).


   4. Summary
Top
 Abstract
 1. Introduction
 2. Renal ischemia reperfusion...
 3. Mechanisms of gender...
 4. Summary
Acknowledgments
 References
 
Though association of these pathways with gender differences in renal I/R has been found, further research is needed to prove their mechanistic involvement in the gender differences noted. Sex hormones and their effects on MAPK, NO, NKA, endothelin, adenosine, KATP channels and Akt may be involved in these gender differences. A better understanding of these mechanisms may allow selective targeting and therapeutic manipulations to help decrease the significant morbidity and mortality caused by ischemic acute renal failure.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Renal ischemia reperfusion...
 3. Mechanisms of gender...
 4. Summary
 Acknowledgments
References
 
This work was supported in part by NIH R01GM070628 (DRM), the Clarian Values Fund (DRM), the Showalter Trust (DRM), and the Cryptic Masons Medical Research Foundation (DRM, MW).


   Notes
 
Time for primary review 20 days


   References
Top
 Abstract
 1. Introduction
 2. Renal ischemia reperfusion...
 3. Mechanisms of gender...
 4. Summary
 Acknowledgments
 References
 

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