AJP - Renal Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol 293: F2-F9, 2007. First published April 11, 2007; doi:10.1152/ajprenal.00072.2007
0363-6127/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/F2    most recent
00072.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bobadilla, N. A.
Right arrow Articles by Gamba, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bobadilla, N. A.
Right arrow Articles by Gamba, G.

INVITED REVIEW

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Norma A. Bobadilla and Gerardo Gamba

Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

Submitted 13 February 2007 ; accepted in final form 10 April 2007


   ABSTRACT
TOP
 ABSTRACT
GRANTS
 REFERENCES
 
Cyclosporine A (CsA), a calcineurin inhibitor, has improved allograft survival in solid organ transplantation and has been increasingly applied in the management of autoimmune diseases. While marked progress has been made in patient and allograft survival rates, clinical use of CsA is often limited by its nephrotoxic effect, which can be presented as two distinct and well-characterized forms: acute and chronic nephrotoxicity. The acute form is characterized by renal vasoconstriction, induced by an imbalance of vasoactive substances release, which leads to renal dysfunction. This form is reversible. The chronic toxicity, in contrast, is characterized by the vasoconstriction plus the development of structural damage that includes arteriolopathy and tubulointerstitial fibrosis that are often not reversible. The exact mechanisms of these deleterious effects are not fully understood, but major advances have occurred over the last few years. Here we review the current literature regarding the pathogenesis and strategies that have been used to ameliorate renal injury in chronic CsA nephrotoxicity. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CsA nephrotoxicity and that spironolactone could be a useful agent to prevent it. These studies and the use of mineralocorticoid receptor blockade are discussed.

cyclosporine A

THE INTRODUCTION OF cyclosporine A (CsA) into clinical transplantation two decades ago as an immunosuppressive agent to prevent allograft rejection lead to a significant improvement in both allograft half-life and patient survival (16). The immunosuppressive action of CsA is mediated by formation of a complex with cyclophilin, which in turn inhibits the activity of protein phosphatase 2B, calcineurin. Hence, CsA is also known as a calcineurin inhibitor. One consequence of calcineurin inactivation is the prevention of dephosphorylation and transfer to the nucleus of nuclear factor of activated T cells (NFAT-1). NFAT-1 is an important regulatory protein that upregulates the transcription and production of IL-2 and other cytokines that promote the growing and proliferation of T and B cells (56).

The therapeutic benefits of calcineurin inhibitors for transplantation and autoimmune diseases have been unfortunately limited by the occurrence of additional effects such as nephrotoxicity, hypertension, hyperkalemia, and increased risk of cardiovascular events (41). The most serious complication of calcineurin inhibitors is the nephrotoxicity that has been reported in both transplant and nontransplant settings (1, 14, 71). Nankivell et al. (39) have shown that after 10 yr of treatment with calcineurin inhibitors, basically all recipient patients presented evidence of chronic nephrotoxicity.

Two forms of CsA renal toxicity have been described: acute and chronic nephropathy. The acute form is characterized by renal vasoconstriction induced by an imbalance of vasoactive substance release, which in turn produces a fall in renal function. This form of toxicity is presented as a reversible acute renal failure when CsA administration is diminished or withdrawn. In contrast, the chronic form of nephrotoxicity is characterized not only by renal vasoconstriction but also by the development of structural damage, including arteriolopathy and tubulointerstitial fibrosis, which is irreversible and may lead to end-stage renal disease (3, 29, 39). This review is focused on studies using CsA, because most of the studies addressing the issue of nephrotoxicity by calcineurin inhibitors have been performed with this agent.

Mechanisms of CsA Nephrotoxicity

Experimental models of CsA nephrotoxicity in rats have been helpful in the study of pathophysiological mechanisms involved in the development and maintenance of renal toxicity. Acute and chronic forms of CsA nephrotoxicity can be reproduced in rats. The acute form is induced by administration of repeated doses of CsA by subcutaneous injection, from a range that varies from 15 to 50 mg·kg–1·day–1 for 7–28 days. The chronic model requires that, in addition to CsA administration at similar doses for at least 15 days, the animals should be fed a low-sodium diet (3, 19, 20, 27, 44, 55), suggesting that for some reason activation of the renin-angiotensin-aldosterone system is required in rats to induce the CsA-related structural injury in the kidney.

Using the models described above, studies in which glomerular hemodynamics were analyzed by renal micropuncture techniques revealed that CsA administration is associated with afferent and efferent arteriolar vasoconstriction, with predominating preglomerular vasoconstriction that results in a significant reduction of renal plasma flow (QA). A reduction of the ultrafiltration coefficient (Kf) has also been observed. The decrease in these two hemodynamic variables lead to a significant reduction of the single-nephron glomerular filtration rate and thus renal dysfunction (7, 10, 11). The precise mechanism by which CsA induced renal vasoconstriction has not been clearly established. Results from several studies indicate that vascular dysfunction induced by CsA results from an increase in vasoconstrictor factors that include endothelin (28), thromboxane (46), and angiotensin II (45, 65) as well as a reduction of vasodilator factors such as prostacyclin (45) and nitric oxide (NO) (10, 11, 17, 34, 69). Thus an imbalance in the release of vasoactive substances seems to be responsible for renal vasoconstriction.

Several factors have been implicated in the development of structural injury during chronic CsA nephrotoxicity. These are 1) activation of the renin-angiotensin-aldosterone system, in which angiotensin II, through the activation of AT1 receptors, not only participates in renal vasoconstriction but also promotes fibrotic processes and the release of aldosterone (47, 58); 2) renal hypoxia that results from renal vasoconstriction induced by CsA, leading to the formation of reactive oxygen species (11, 34) that cause cellular injury and promote cellular death by apoptosis (77, 78); and 3) upregulation of transforming growth factor-beta (TGF-beta), which promotes renal fibrosis by increasing the production and decreasing the degradation of extracellular matrix proteins (20, 33, 58, 72).

Strategies to Prevent or Reduce Chronic CsA Nephrotoxicity

Because the use of CsA as an immunosuppressive agent to prevent allograft rejection has been limited by its toxic effects, several groups have studied potential strategies to prevent or reduce CsA nephrotoxicity. Acute toxicity is reversible, while chronic toxicity in which histological changes occur is nonreversible and increases the risk of end-stage renal disease. Thus most of the studies have been performed using the chronic model of toxicity, in which rats are fed a low-salt diet during the period of CsA administration. Results of these strategies on renal function and tubulointerstitial fibrosis are shown in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1. Pharmacological treatments used to reduce or prevent chronic CsA nephrotoxicity

 
The vasoconstrictor effect of CsA on renal vasculature has been shown to be involved in the pathogenesis of CsA toxicity. As we mentioned before, a group of strategies have been developed toward blocking the effect of vasoconstrictor factors such as losartan as an antagonist of angiotensin II receptor 1 (64), BQ123 for its properties as endothelin receptors blocker (26), and L-arginine as substrate for NO synthase, producing NO to counteract renal vasoconstriction (5, 57). Although losartan was able to reduce tubulointerstitial fibrosis by ~50%, no improvement was observed in renal function. In fact, a further decrease in creatinine clearance was observed in rats treated with CsA and losartan, probably secondary to the losartan-induced fall in efferent resistance. Antagonism of both receptors, endothelin A and B, with BQ123 improved renal function by ~30% but was unable to reduce renal structural injury. These observations agree with Kon et al. (28), who suggested that endothelin is at least partially responsible for afferent vasoconstriction. However, the slight increase in renal function was not associated with improvement of renal structural damage. In contrast, chronic L-arginine administration increased renal function by ~70% and reduced tubulointerstitial injury by ~50%. This protective effect was associated with a reduction of vascular endothelial growth factor (VEGF) and suggests that the reestablishment of renal blood flow due to increased availability of NO was associated with lesser structural injury.

A second group of studies included two different treatments with anti-inflammatory drugs such as pentosan polysulfate (55) and mycophenolate mofetil (61). Schwadler et al. (55) observed that pentosan polysulfate was able to reduce arteriolar lesions and tubulointerstitial fibrosis by ~45%, but this treatment did not prevent the CsA-induced decrease in creatinine clearance. Shihab et al. (61) reported that mycophenolate mofetil is capable of improving neither renal function nor structural injury produced by CsA. Thus anti-inflammatory drugs are not able to improve renal function in CsA-treated rats and had limited benefit in preventing renal structural injury.

A third group of studies included drugs with antifibrotic properties such as the TGF-beta antibody, statins, pirfenidone, and hepatocyte growth factor. Because of the central role of TGF-beta in the development of renal injury induced by calcineurin inhibitors, the effect TGF-beta-neutralizing monoclonal antibody administration was studied. As Table 1 shows, this strategy reduced renal structural injury by ~40%. Although renal function was not determined, serum creatinine levels were significantly lower in mice that received the TGF-beta antibody than in untreated mice, suggesting that neutralization of TGF-beta, in addition to expected reduction in renal fibrosis, also improved renal function by a mechanism that remains to be determined. Previous studies in cultured mesangial cells (23) and in rats with diabetic nephropathy (22) have shown that TGF-beta upregulation induced glomerular injury through activation of calcineurin, which in turn induced greater NFAT translocation to the nucleus, resulting in mesangial proliferation and extracellular matrix (ECM) accumulation. In the diabetic rats, these effects were reduced by CsA administration in the glomerular but not in tubulointerstitial area (22), suggesting that calcineurin activation promotes ECM accumulation in the glomerulus. On the other hand, calcineurin inhibitors are associated with TGF-beta overexpression and tubulointerstitial, but not glomerular, ECM accumulation (58, 62), suggesting that calcineurin activity results in different effects on ECM accumulation between the glomerulus and tubulointerstitium. Pravastatin, a drug with anti-inflammatory and antifibrotic properties, was evaluated in this sort of kidney injury. As shown in Table 1, pravastatin administration improved renal function by 70% and reduced tubulointerstitial fibrosis by ~55%. Mechanisms implicated were suppression of osteopontin, TGF-beta, and intrarenal C-reactive protein expression together with higher eNOS expression (70). However, the beneficial effect of pravastatin in very high doses (20 mg/kg) was not observed in rats that received lower doses (5 mg/kg). Another antifibrotic agent that has been tested in chronic CsA nephrotoxicity is pirfenidone. The mechanism of action of this compound is unclear, but available data suggest that pirfenidone inhibits the actions of TGF-beta. Shihab et al. (59, 60) showed that simultaneous administration of pirfenidone to CsA-treated and salt-depleted rats significantly reduced tubulointerstitial fibrosis by ~50%. This antifibrotic effect was accompanied by a reduction of TGF-beta protein expression and matrix deposition, as well as by a reduction of cell death by apoptosis and expression of regulatory genes of apoptosis. Finally, hepatocyte growth factor has also been reported to protect against renal injury as an antifibrotic factor. Mizui et al. (38) showed a slight reduction of renal fibrosis by hepatocyte growth factor gene transfer in chronic CsA nephrotoxicity (~25%), an effect that was accompanied by a reduction of TGF-beta mRNA levels and apoptosis. Thus antifibrotic approaches such as TGF-beta antibody, pravastatin, pirfenidone, and hepatocyte growth factor can be of help in reducing renal fibrosis.

Supplementation of magnesium is another strategy that has been shown to be helpful in correcting hypomagnesemia in Sprague-Dawley rats with chronic CsA nephrotoxicity (37). Asai et al. (6) observed that magnesium supplementation prevented renal dysfunction induced by CsA. In this study, vehicle-treated rats had a creatinine clearance of 2.1 ± 04 ml/min. Renal function was decreased by CsA to 0.8 ± 0.1 ml/min, and this effect was partially reversed by magnesium supplementation to a value of 1.7 ± 0.1 ml/min. Simultaneously, renal structural damage was also prevented. Authors observed that rats treated with CsA in which magnesium was supplemented exhibited a reduction of osteopontin, monocyte chemoattractant protein-1, TGF-beta, and endothelin mRNA levels, associated with a decrease in monocyte/macrophage influx into renal tissue. Because the beneficial effects of magnesium supplementation were not observed when the renin-angiotensin system was inhibited with the angiotensin-converting enzyme inhibitor benazepril, the authors concluded that the protective effect of magnesium supplementation was independent of angiotensin II. The mechanism by which magnesium supplementation was able to prevent CsA toxicity was not elucidated. Interestingly, however, the protective effect of magnesium supplementation was not observed in two other studies. Burdmann et al. (12) and Andoh et al. (4) also analyzed the effect of magnesium supplementation in Sprague-Dawley rats with chronic CsA nephrotoxicity. Although in both studies hypomagnesemia was successfully corrected by exposing rats to drinking water containing 2% MgCl2, the reduction in glomerular filtration rate was not prevented by this maneuver. In addition, we have observed that hypomagnesemia does not occur in Wistar rats with acute or chronic CsA nephrotoxicity. In our experience, plasma magnesium levels in vehicle- and CsA-treated animals under a low-sodium diet for 21 days were 2.1 ± 0.1 and 2.6 ± 0.1 mg/dl, respectively. Thus in Wistar rats CsA nephrotoxicity is developed in the absence of hypomagnesemia, suggesting that, at least in this model, CsA toxicity is not related to magnesium deficiency.

Finally, in clinical practice, there are also several studies that have evaluated different strategies to reduce CsA nephrotoxicity, but only a few of them focused on chronic nephropathy. Use of the calcium channel blocker nifedipine is one strategy that has shown a beneficial effect on renal dysfunction and interstitial fibrosis in patients treated with CsA for 6 and 12 mo after transplantation (35), suggesting that renal vasodilatation induced by nifedipine protects the kidney from detrimental CsA actions. Another strategy reported is dietary supplementation with fish oil. van der Heide et al. (68) observed that recipients of a primary cadaveric kidney transplant who were treated with CsA and who ingested fish oil daily during the first postoperative year had higher glomerular filtration rate and renal plasma flow than those not ingesting fish oil. However, a more recent randomized, double-blind, placebo-controlled in transplant patients taking CsA showed no beneficial effect of fish oil on glomerular filtration rate and renal plasma flow, as well as on renal histopathology. In addition, two studies tested the effect of randomized pentoxifylline administration, a hemorrheological agent, to cardiac transplant patients treated with CsA. Renal dysfunction induced by CsA was similar between the pentoxifylline and placebo group (21, 74). A similar effect has been observed in CsA-treated renal transplant recipients also receiving CGS 12970, a thromboxane synthase inhibitor (63). Thus, of all potential preventive treatments tested in humans to reduce CsA nephrotoxicity, the only one that showed beneficial effects was the use of renal vasodilators like calcium channel blockers.

Role of Aldosterone in CsA Nephrotoxicity

Table 1 shows that the blockade of aldosterone receptors with spironolactone has been shown to be a successful strategy to ameliorate CsA nephropathy. In recent years, there has been a growing interest in the role of aldosterone and mineralocorticoid receptors (MR) in the pathophysiology of cardiovascular and renal diseases. The role of aldosterone in promoting cardiovascular injury is underlined by the Randomized Aldactone Evaluation Study (RALES) (49) and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trials (48). In these studies, it was observed that addition of MR blockers spironolactone or eplerenone to standard therapy resulted in reduced cardiac mortality that could not be explained solely by blood pressure reduction. In addition, recent animal and clinical studies support a beneficial effect of MR blockade on the progression of renal injury. In rats, MR antagonists markedly ameliorated glomerular and/or tubulointerstitial injury in several models of nephropathy, including spontaneously hypertensive stroke-prone rats (50, 51), angiotensin II and NO synthase inhibitor-treated rats (52), aldosterone-treated rats (25), and in a ureteral obstruction model (66). Moreover, Aldigier et al. (2) reported that MR blockade not only reduced the development of glomerulosclerosis but also induced regression of existing glomerulosclerosis in rats after 5/6 nephrectomy. In humans, pilot studies showed that the addition of spironolactone to angiotensin-converting enzyme inhibitors had no hemodynamic effects but markedly reduced proteinuria in patients with renal failure (8) and in patients with type 2 diabetes (53). The protective effect of spironolactone in patients with mild renal insufficiency has recently been corroborated by a large double-blind, placebo-controlled randomized trial (15).

Given the evidence that MR blockade protects the kidney in several models of renal disease, Feria et al. (20) analyzed the effect of spironolactone administration in rats with chronic CsA nephrotoxicity. Administration of CsA during 21 days induced renal structural damage characterized by arteriolopathy and tubulointerstitial fibrosis. This effect was associated with an upregulation of TGF-beta, fibronectin, and collagen I and IV mRNA levels. In contrast, rats that received simultaneous administration of CsA and spironolactone presented a significant reduction of arteriolopathy and tubulointerstitial fibrosis. This renoprotective effect was related to the prevention of overexpression of TGF-beta and extracellular matrix proteins. Interestingly, as shown in Fig. 1A, Feria et al. (20) also observed that spironolactone administration completely prevented the reduction of creatinine clearance, suggesting that aldosterone is an important mediator of both functional and structural injury in this model of nephropathy. We later observed that protection conferred by spironolactone was associated with prevention of the CsA-induced pro-renin mRNA upregulation and ETB receptor downregulation (44).


Figure 1
View larger version (22K):
[in this window]
[in a new window]

  		Fig. 1. Protective effect of spironolactone on cyclosporine (CsA) toxicity. A: creatine clearance (CCR) in chronic toxicity. B and C: glomerular filtration rate (GFR) and renal blood flow (RBF) in acute toxicity, respectively. D: creatinine clearance in already preexisting chronic CsA nephrotoxicity. V, vehicle-treated rats; Sp, spironolactone-treated rats; CsA, cyclosporine-treated rats; CsA+Sp, rats that received cyclosporine and spironolactone. Data are modified from Refs. 20, 43 and 44. *P < 0.05 vs. the same group at 0 days. **P < 0.05 vs. the same group at 18 days.

 
The fact that spironolactone not only reduced structural injury in chronic CsA nephrotoxicity but also completely prevented renal dysfunction suggested that aldosterone is implicated in regulating renal vascular tone in this model. Since acute CsA nephrotoxicity results mainly from renal vasoconstriction, Perez-Rojas et al. (44) studied the effect of spironolactone on renal blood flow and glomerular filtration rate in rats treated with CsA for 7 days, in the absence of a low-salt diet, to produce the reversible CsA-acute model. As shown in Fig. 1, B and C, it was observed that spironolactone administration completely prevented the fall in glomerular filtration rate as measured by inulin clearance. This effect was accompanied by the reestablishment of renal blood flow. A similar improvement of renal blood flow and function by aldosterone blockade in acute CsA nephrotoxicity was recently reproduced by Nielsen et al. (40). The mineralocorticoid receptor is a protein complex that includes a steroid-binding protein receptor and heat shock proteins (Hsps) of 56, 70, and 90 kDa. Interestingly, Tumlin et al. (67) reported that when steroid hormone bound to its receptor, the release of the Hsps complex is able to activate calcineurin phosphatase activity. Also, it has been demonstrated that calcineurin might regulate Na+-K+-ATPase activity through dephosphorylation of its catalytic subunit (30). These studies suggest that aldosterone could mediate actions through at least two different mechanisms: by the classic pathway at the transcriptional level and by releasing the Hsps complex that could change the activity of different proteins including the phosphatase calcineurin. These findings, together with our previous observations of chronic CsA toxicity, showed that mineralocorticoid receptor blockade prevented renal vasoconstriction, suggesting that aldosterone participates in CsA renal homodynamic effect that could be mediated by both mechanisms describe before. Thus our findings in acute and chronic models of CsA nephrotoxicity indicated that spironolactone is an effective prophylactic agent to prevent the development of CsA nephrotoxicity. Finally, Perez-Rojas et al. (43) analyzed whether spironolactone blockade can contribute to prevent the progression of existing tubulointerstitial injury and renal dysfunction in the model of chronic CsA nephropathy. As shown in Fig. 1D, once chronic CsA nephrotoxicity was established after 18 days of treatment and confirmed through renal function and structural analysis, one group of rats simultaneously received CsA and spironolactone during an additional 18 days and was compared with a group that received only CsA for a similar period of time. It was observed that MR blockade increased rat survival, and although renal dysfunction already established in CsA-treated rats was not reversed by spironolactone, this treatment was able to avoid further renal function deterioration. On a structural level, spironolactone produced significant renal protection associated with a reduction of arteriolar thickening, apoptosis, and the area affected by tubulointerstitial fibrosis. The renoprotection conferred by spironolactone in rats with preexisting chronic CsA nephrotoxicity was associated with a reduction of TGF-beta and procaspase-3 mRNA levels.

The potential role of aldosterone as a promoter of vasoconstriction was originally suggested by the observations that primary aldosteronism, a disease due to oversecretion of aldosterone, is associated with impaired vascular reactivity (9, 18). In addition, it was reported by Gros et al. (24) that acute aldosterone exposure induced a dose-dependent vasoconstriction through myosin light chain phosphorylation in clonal adult human vascular smooth muscle cells. This effect was prevented by spironolactone, suggesting that aldosterone-mediating vasoconstriction may represent an important pathophysiological mechanism of vascular disease. The mechanisms by which aldosterone increases vascular resistance has not been elucidated, but some studies suggest possible mechanisms, such as an increased catecholamine vasoconstrictor effect (73) and upregulation of angiotensin II receptors (54, 75, 76). A recent report indicates that aldosterone induces a downregulation of endothelial glucose-6-phosphate dehydrogenase that results in impaired oxidative stress and decreased NO availability. Interestingly, these effects of aldosterone were completely prevented by spironolactone (31). In support to this, we have recently shown that spironolactone completely prevented renal acute injury induced by ischemia-reperfusion by a mechanism that involved preservation of renal plasma flow, reestablishment of urinary NO2/NO3 excretion that was accompanied by increased expression of eNOS and phosphorylation at its residue S1177, as well as by a reduction of lipoperoxidation and cell apoptotic death, indicating indeed that aldosterone also participates in hypoperfusion observed in this model (36).

A New Scheme of CsA-Induced Nephrotoxicity

As shown in Table 1, there is a clear dissociation between improvement of structural changes and normalization of renal function. Some strategies, like antifibrotic agents, were able to improve renal structural damage but had no beneficial effect on renal function. In contrast, strategies such as L-arginine (5, 57) and spironolactone (20, 43, 44), which improved renal function probably due to an effect on vascular resistances, had an additional beneficial effect on structural injury, suggesting that the increase in vascular resistances, with consequent renal ischemia, seems to be a major pathophysiological mechanism involved in the development of structural injury. In this regard, we propose that aldosterone plays a central role in the establishment of renal dysfunction and structural injury observed in chronic CsA nephrotoxicity (Fig. 2). The cascade of events seems to begin with the well-known effect of CsA, inducing an imbalance of vasoactive substances release, such as an increase in endothelin, thromboxane, and angiotensin II and a decrease in prostacyclin and NO, resulting in renal vasoconstriction (for a review, see Refs. 13 and 42). Angiotensin II stimulates aldosterone secretion from adrenal glands, although it is also possible that local synthesis of aldosterone in the kidney might be also stimulated. Despite the increase in vasoconstrictor factors induced by CsA, we propose that aldosterone itself could be the major player in producing renal vasoconstriction, since aldosterone receptor blockade completely prevented the fall in renal plasma flow and glomerular filtration rate induced by CsA (20, 44). The resulting renal vasoconstriction is responsible for both renal dysfunction and hypoxia observed during CsA nephrotoxicity. It is also known that renal ischemia promotes greater generation of reactive oxygen species that contribute to structural damage by increasing apoptosis and cellular tubular injury. We suggest that aldosterone also participates in the development of structural injury through increased TGF-beta expression and cellular death by apoptosis. However, in contrast to renal vasoconstriction, interstitial inflammation and macrophage infiltration are not only caused by aldosterone. Instead, CsA and angiotensin II themselves may contribute to the development of tubulointerstitial fibrosis. As a consequence, although aldosterone receptor blockade with spironolactone is able to fully reverse the renal dysfunction induced by CsA, it does not completely prevent structural injury.


Figure 2
View larger version (20K):
[in this window]
[in a new window]

  		Fig. 2. Role of aldosterone in the pathophysiology of CsA nephrotoxicity. ROS, reactive oxygen species; TGF-beta, transforming growth factor-beta.

 

   GRANTS
TOP
 ABSTRACT
 GRANTS
REFERENCES
 
This work was supported by Mexican Council of Science and Technology (CONACYT) Grant 24851 and Grant DGAPA IN228206-3 from National University of Mexico (to N. A. Bobadilla) and National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-064635 grant (to G. Gamba).


   FOOTNOTES
 

Address for reprint requests and other correspondence: N. A. Bobadilla or G. Gamba, Molecular Physiology Unit, Vasco de Quiroga No. 15, Tlalpan, 14000 México City, Mexico (e-mail: nab{at}biomedicas.unam.mx or gamba{at}biomedicas.unam.mx)


   REFERENCES
TOP
 ABSTRACT
 GRANTS
 REFERENCES
 

  1. Abramowicz D, Wissing KM, Broeders N. Nephrotoxicity of calcineurin inhibitors: new therapeutic approaches. Transplant Proc 32: 3S–5S, 2000.[Web of Science][Medline]
  2. Aldigier JC, Kanjanbuch T, Ma LJ, Brown NJ, Fogo AB. Regression of existing glomerulosclerosis by inhibition of aldosterone. J Am Soc Nephrol 16: 3306–3314, 2005.[Abstract/Free Full Text]
  3. Andoh TF, Burdmann EA, Bennett WM. Nephrotoxicity of immunosuppressive drugs: experimental and clinical observations. Semin Nephrol 17: 34–45, 1997.[Web of Science][Medline]
  4. Andoh TF, Burdmann EA, Fransechini N, Houghton DC, Bennett WM. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int 50: 1110–1117, 1996.[Web of Science][Medline]
  5. Andoh TF, Gardner MP, Bennett WM. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation 64: 1236–1240, 1997.[CrossRef][Web of Science][Medline]
  6. Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation 74: 784–791, 2002.[CrossRef][Web of Science][Medline]
  7. Barros EJ, Boim MA, Ajzen H, Ramos OL, Schor N. Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity. Kidney Int 32: 19–25, 1987.[Web of Science][Medline]
  8. Bianchi S, Bigazzi R, Campese VM. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis 46: 45–51, 2005.[CrossRef][Web of Science][Medline]
  9. Blacher J, Amah G, Girerd X, Kheder A, Ben Mais H, London GM, Safar ME. Association between increased plasma levels of aldosterone and decreased systemic arterial compliance in subjects with essential hypertension. Am J Hypertens 10: 1326–1334, 1997.[Web of Science][Medline]
  10. Bobadilla NA, Gamba G, Tapia E, Garcia-Torres R, Bolio A, Lopez-Zetina P, Herrera-Acosta J. Role of NO in cyclosporin nephrotoxicity: effects of chronic NO inhibition and NO synthases gene expression. Am J Physiol Renal Physiol 274: F791–F798, 1998.[Abstract/Free Full Text]
  11. Bobadilla NA, Tapia E, Franco M, Lopez P, Mendoza S, Garcia-Torres R, Alvarado JA, Herrera-Acosta J. Role of nitric oxide in renal hemodynamic abnormalities of cyclosporin nephrotoxicity. Kidney Int 46: 773–779, 1994.[Web of Science][Medline]
  12. Burdmann EA, Andoh TF, Lindsley J, Houghton DC, Bennett WM. Effects of oral magnesium supplementation on acute experimental cyclosporin nephrotoxicity. Nephrol Dial Transplant 9: 16–21, 1994.[Abstract/Free Full Text]
  13. Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol 23: 465–476, 2003.[CrossRef][Web of Science][Medline]
  14. Campistol JM, Sacks SH. Mechanisms of nephrotoxicity. Transplantation 69: SS5–SS10, 2000.[Web of Science][Medline]
  15. Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ. Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin ii receptor blocker. Clin J Am Soc Nephrol 1: 256–262, 2006.[CrossRef][Medline]
  16. de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 35: 333–346, 2000.[Web of Science][Medline]
  17. Diederich D, Yang Z, Luscher TF. Chronic cyclosporine therapy impairs endothelium-dependent relaxation in the renal artery of the rat. J Am Soc Nephrol 2: 1291–1297, 1992.[Abstract]
  18. Duprez DA, De Buyzere ML, Rietzschel ER, Taes Y, Clement DL, Morgan D, Cohn JN. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J 19: 1371–1376, 1998.[Abstract/Free Full Text]
  19. Elzinga LW, Rosen S, Bennett WM. Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake. J Am Soc Nephrol 4: 214–221, 1993.[Abstract]
  20. Feria I, Pichardo I, Juarez P, Ramirez V, Gonzalez MA, Uribe N, Garcia-Torres R, Lopez-Casillas F, Gamba G, Bobadilla NA. Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity. Kidney Int 63: 43–52, 2003.[Web of Science][Medline]
  21. Frantz RP, Edwards BS, Olson LJ, Schwab MK, Adams TF, Textor SC, Daly RC, McGregor CG, Rodeheffer RJ. Effects of pentoxifylline on renal function and blood pressure in cardiac transplant recipients: a randomized trial. Transplantation 63: 1607–1610, 1997.[CrossRef][Web of Science][Medline]
  22. Gooch JL, Barnes JL, Garcia S, Abboud HE. Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation. Am J Physiol Renal Physiol 284: F144–F154, 2003.[Abstract/Free Full Text]
  23. Gooch JL, Gorin Y, Zhang BX, Abboud HE. Involvement of calcineurin in transforming growth factor-beta-mediated regulation of extracellular matrix accumulation. J Biol Chem 279: 15561–15570, 2004.[Abstract/Free Full Text]
  24. Gros R, Ding Q, Armstrong S, O'Neil C, Pickering JG, Feldman RD. Rapid effects of aldosterone on clonal human vascular smooth muscle cells. Am J Physiol Cell Physiol 292: C788–C794, 2007.[Abstract/Free Full Text]
  25. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int 66: 1–9, 2004.[CrossRef][Web of Science][Medline]
  26. Hunley TE, Fogo A, Iwasaki S, Kon V. Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity. J Am Soc Nephrol 5: 1718–1723, 1995.[Abstract]
  27. Jackson NM, Hsu CH, Visscher GE, Venkatachalam MA, Humes HD. Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity. J Pharmacol Exp Ther 242: 749–756, 1987.[Abstract/Free Full Text]
  28. Kon V, Sugiura M, Inagami T, Harvie BR, Ichikawa I, Hoover RL. Role of endothelin in cyclosporine-induced glomerular dysfunction. Kidney Int 37: 1487–1491, 1990.[Web of Science][Medline]
  29. Kopp JB, Klotman PE. Cellular and molecular mechanisms of cyclosporin nephrotoxicity. J Am Soc Nephrol 1: 162–179, 1990.[Abstract]
  30. Lea JP, Sands JM, McMahon SJ, Tumlin JA. Evidence that the inhibition of Na+/K+-ATPase activity by FK506 involves calcineurin. Kidney Int 46: 647–652, 1994.[Web of Science][Medline]
  31. Leopold JA, Dam A, Scribner AW, Liao R, Handy DE, Stanton RC, Pitt B, Loscalzo JL. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med 13: 189–197, 2007.[CrossRef][Web of Science][Medline]
  32. Li C, Yang CW, Park JH, Lim SW, Sun BK, Jung JY, Kim SB, Kim YS, Kim J, Bang BK. Pravastatin treatment attenuates interstitial inflammation and fibrosis in a rat model of chronic cyclosporine-induced nephropathy. Am J Physiol Renal Physiol 286: F46–F57, 2004.[Abstract/Free Full Text]
  33. Ling H, Li X, Jha S, Wang W, Karetskaya L, Pratt B, Ledbetter S. Therapeutic role of TGF-beta-neutralizing antibody in mouse cyclosporin A nephropathy: morphologic improvement associated with functional preservation. J Am Soc Nephrol 14: 377–388, 2003.[Abstract/Free Full Text]
  34. Lopez-Ongil S, Saura M, Rodriguez-Puyol D, Rodriguez-Puyol M, Lamas S. Regulation of endothelial NO synthase expression by cyclosporin A in bovine aortic endothelial cells. Am J Physiol Heart Circ Physiol 271: H1072–H1078, 1996.[Abstract/Free Full Text]
  35. McCulloch TA, Harper SJ, Donnelly PK, Moorhouse J, Bell PR, Walls J, Feehally J, Furness PN. Influence of nifedipine on interstitial fibrosis in renal transplant allografts treated with cyclosporin A. J Clin Pathol 47: 839–842, 1994.[Abstract/Free Full Text]
  36. Mejia-Vilet JM, Ramirez V, Cruz C, Uribe N, Gamba G, Bobadilla NA. Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone. Am J Physiol Renal Physiol. In press.
  37. Miura K, Nakatani T, Asai T, Yamanaka S, Tamada S, Tashiro K, Kim S, Okamura M, Iwao H. Role of hypomagnesemia in chronic cyclosporine nephropathy. Transplantation 73: 340–347, 2002.[CrossRef][Web of Science][Medline]
  38. Mizui M, Isaka Y, Takabatake Y, Mizuno S, Nakamura T, Ito T, Imai E, Hori M. Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity. Kidney Int 65: 2041–2053, 2004.[CrossRef][Web of Science][Medline]
  39. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 349: 2326–2333, 2003.[Abstract/Free Full Text]
  40. Nielsen FT, Jensen BL, Skøtt O, Bie P. Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporine A nephrotoxicity in the rat (Abstract). J Am Soc Nephrol 17: 310A, 2006.
  41. Olyaei AJ, de Mattos AM, Bennett WM. Immunosuppressant-induced nephropathy: pathophysiology, incidence and management. Drug Saf 21: 471–488, 1999.[CrossRef][Web of Science][Medline]
  42. Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care 7: 384–389, 2001.[CrossRef][Medline]
  43. Perez-Rojas J, Blanco JA, Cruz C, Trujillo J, Vaidya VS, Uribe N, Bonventre JV, Gamba G, Bobadilla NA. Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity. Am J Physiol Renal Physiol 292: F131–F139, 2007.[Abstract/Free Full Text]
  44. Perez-Rojas JM, Derive S, Blanco JA, Cruz C, Martinez de la Maza L, Gamba G, Bobadilla NA. Renocortical mRNA expression of vasoactive factors during spironolactone protective effect in chronic cyclosporine nephrotoxicity. Am J Physiol Renal Physiol 289: F1020–F1030, 2005.[Abstract/Free Full Text]
  45. Perico N, Benigni A, Bosco E, Rossini M, Orisio S, Ghilardi F, Piccinelli A, Remuzzi G. Acute cyclosporine A nephrotoxicity in rats: which role for renin- angiotensin system and glomerular prostaglandins? Clin Nephrol 25, Suppl 1: S83–S88, 1986.[Web of Science][Medline]
  46. Perico N, Benigni A, Zoja C, Delaini F, Remuzzi G. Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A. Am J Physiol Renal Fluid Electrolyte Physiol 251: F581–F587, 1986.[Abstract/Free Full Text]
  47. Pichler RH, Franceschini N, Young BA, Hugo C, Andoh TF, Burdmann EA, Shankland SJ, Alpers CE, Bennett WM, Couser WG. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J Am Soc Nephrol 6: 1186–1196, 1995.[Abstract]
  48. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348: 1309–1321, 2003.[Abstract/Free Full Text]
  49. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341: 709–717, 1999.[Abstract/Free Full Text]
  50. Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension 31: 451–458, 1998.[Abstract/Free Full Text]
  51. Rocha R, Chander PN, Zuckerman A, Stier CT Jr. Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. Hypertension 33: 232–237, 1999.[Abstract/Free Full Text]
  52. Rocha R, Stier CT Jr, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler GK. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology 141: 3871–3878, 2000.[Abstract/Free Full Text]
  53. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 41: 64–68, 2003.[Abstract/Free Full Text]
  54. Schiffrin EL, Franks DJ, Gutkowska J. Effect of aldosterone on vascular angiotensin II receptors in the rat. Can J Physiol Pharmacol 63: 1522–1527, 1985.[Web of Science][Medline]
  55. Schwedler SB, Bobadilla N, Striker LJ, Vaamonde CA, Herrera-Acosta J, Striker GE. Pentosan polysulfate treatment reduces cyclosporine-induced nephropathy in salt-depleted rats. Transplantation 68: 1583–1588, 1999.[Web of Science][Medline]
  56. Shaw KT, Ho AM, Raghavan A, Kim J, Jain J, Park J, Sharma S, Rao A, Hogan PG. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci USA 92: 11205–11209, 1995.[Abstract/Free Full Text]
  57. Shihab FS, Bennett WM, Isaac J, Yi H, Andoh TF. Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity. Kidney Int 63: 522–533, 2003.[CrossRef][Web of Science][Medline]
  58. Shihab FS, Bennett WM, Tanner AM, Andoh TF. Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy. Kidney Int 52: 660–673, 1997.[Web of Science][Medline]
  59. Shihab FS, Bennett WM, Yi H, Andoh TF. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Am J Transplant 2: 111–119, 2002.[CrossRef][Web of Science][Medline]
  60. Shihab FS, Bennett WM, Yi H, Andoh TF. Effect of pirfenidone on apoptosis-regulatory genes in chronic cyclosporine nephrotoxicity. Transplantation 79: 419–426, 2005.[CrossRef][Web of Science][Medline]
  61. Shihab FS, Bennett WM, Yi H, Choi SO, Andoh TF. Mycophenolate mofetil ameliorates arteriolopathy and decreases transforming growth factor-beta1 in chronic cyclosporine nephrotoxicity. Am J Transplant 3: 1550–1559, 2003.[CrossRef][Web of Science][Medline]
  62. Shihab FS, Yi H, Bennett WM, Andoh TF. Effect of nitric oxide modulation on TGF-beta1 and matrix proteins in chronic cyclosporine nephrotoxicity. Kidney Int 58: 1174–1185, 2000.[CrossRef][Web of Science][Medline]
  63. Smith SR, Kubacki VB, Rakhit A, Martin LL, Schaffer AV, Jasani MK, Hefty DJ, Johnston T, Cannon C, Bennett WM. Chronic thromboxane synthase inhibition with CGS 12970 in human cyclosporine nephrotoxicity. Transplantation 56: 1422–1426, 1993.[Web of Science][Medline]
  64. Thomas SE, Andoh TF, Pichler RH, Shankland SJ, Couser WG, Bennett WM, Johnson RJ. Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int 53: 897–908, 1998.[CrossRef][Web of Science][Medline]
  65. Thomson AW, McAuley FT, Whiting PH, Simpson JG. Angiotensin-converting enzyme inhibition or aldosterone antagonism reduces cyclosporine nephrotoxicity in the rat. Transplant Proc 19: 1242–1243, 1987.[Web of Science][Medline]
  66. Trachtman H, Weiser AC, Valderrama E, Morgado M, Palmer LS. Prevention of renal fibrosis by spironolactone in mice with complete unilateral ureteral obstruction. J Urol 172: 1590–1594, 2004.[CrossRef][Web of Science][Medline]
  67. Tumlin JA, Lea JP, Swanson CE, Smith CL, Edge SS, Someren JS. Aldosterone and dexamethasone stimulate calcineurin activity through a transcription-independent mechanism involving steroid receptor-associated heat shock proteins. J Clin Invest 99: 1217–1223, 1997.[Web of Science][Medline]
  68. van der Heide JJ, Bilo HJ, Donker JM, Wilmink JM, Tegzess AM. Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants. N Engl J Med 329: 769–773, 1993.[Abstract/Free Full Text]
  69. Vaziri ND, Ni Z, Zhang YP, Ruzics EP, Maleki P, Ding Y. Depressed renal and vascular nitric oxide synthase expression in cyclosporine-induced hypertension. Kidney Int 54: 482–491, 1998.[CrossRef][Web of Science][Medline]
  70. Venema RC, Venema VJ, Ju H, Harris MB, Snead C, Jilling T, Dimitropoulou C, Maragoudakis ME, Catravas JD. Novel complexes of guanylate cyclase with heat shock protein 90 and nitric oxide synthase. Am J Physiol Heart Circ Physiol 285: H669–H678, 2003.[Abstract/Free Full Text]
  71. Vercauteren SB, Bosmans JL, Elseviers MM, Verpooten GA, De Broe ME. A meta-analysis and morphological review of cyclosporine-induced nephrotoxicity in auto-immune diseases. Kidney Int 54: 536–545, 1998.[CrossRef][Web of Science][Medline]
  72. Vieira JM Jr, Noronha IL, Malheiros DM, Burdmann EA. Cyclosporine-induced interstitial fibrosis and arteriolar TGF-beta expression with preserved renal blood flow. Transplantation 68: 1746–1753, 1999.[CrossRef][Web of Science][Medline]
  73. Wang W, McClain JM, Zucker IH. Aldosterone reduces baroreceptor discharge in the dog. Hypertension 19: 270–277, 1992.[Abstract/Free Full Text]
  74. White JR Jr, Rockwood T, Wilson D, Bettesworth L, Icenogle T. The effects of pentoxifylline on the prevention of cyclosporine-induced nephrotoxicity in cardiac transplant patients. Clin Ther 16: 673–679, 1994.[Web of Science][Medline]
  75. Wu MS, Yang CW, Chang CT, Bens M, Vandewalle A. Cyclosporin increases the density of angiotensin II subtype 1 (AT1) receptors in mouse medullary thick ascending limb cells. Nephrol Dial Transplant 18: 1458–1465, 2003.[Abstract/Free Full Text]
  76. Xiao F, Puddefoot JR, Barker S, Vinson GP. Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation. Hypertension 44: 340–345, 2004.[Abstract/Free Full Text]
  77. Zhong Z, Arteel GE, Connor HD, Yin M, Frankenberg MV, Stachlewitz RF, Raleigh JA, Mason RP, Thurman RG. Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine. Am J Physiol Renal Physiol 275: F595–F604, 1998.[Abstract/Free Full Text]
  78. Zhong Z, Connor HD, Yin M, Moss N, Mason RP, Bunzendahl H, Forman DT, Thurman RG. Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat kidney. Mol Pharmacol 56: 455–463, 1999.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
M. Kato, M. Akao, M. Matsumoto-Ida, T. Makiyama, M. Iguchi, T. Takeda, S. Shimizu, and T. Kita
The targeting of cyclophilin D by RNAi as a novel cardioprotective therapy: evidence from two-photon imaging
Cardiovasc Res, July 15, 2009; 83(2): 335 - 344.
[Abstract] [Full Text] [PDF]

Home page
 CJASNHome page
M. Naesens, D. R. J. Kuypers, and M. Sarwal
Calcineurin Inhibitor Nephrotoxicity
Clin. J. Am. Soc. Nephrol., February 1, 2009; 4(2): 481 - 508.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
S. Lee, W. Kim, D. H. Kim, S.-O. Moon, Y. J. Jung, A. S. Lee, K. P. Kang, K. Y. Jang, S. Y. Lee, M. J. Sung, et al.
Protective effect of COMP-angiopoietin-1 on cyclosporine-induced renal injury in mice
Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2784 - 2794.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
G. Capasso, C. I. Di Gennaro, F. D. Ragione, C. Manna, R. Ciarcia, S. Florio, A. Perna, R. M. Pollastro, S. Damiano, O. Mazzoni, et al.
In vivo effect of the natural antioxidant hydroxytyrosol on cyclosporine nephrotoxicity in rats
Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1186 - 1195.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/F2    most recent
00072.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bobadilla, N. A.
Right arrow Articles by Gamba, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bobadilla, N. A.
Right arrow Articles by Gamba, G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.