Effect of pentoxifylline on cyclosporine-induced nephrotoxicity in rats

Effect of unique hemorrheologic agent pentoxifylline (PTX) was investigated on cyclosporine (CsA) induced nephrotoxicity in rats. Compared to saline control, CsA produced significant increase in blood urea and serum creatinine. Pentoxifylline treatment prevented the CsA-induced rise in blood urea and serum creatinine. Creatinine clearance (Ccr) and lithium clearance (Licr) was decreased with CsA. PTX treatment prevented the CsA-induced decrease in Ccr and Licr. Malondialdehyde (MDA) was increased with CsA compared to saline treated animals. PTX prevented the CsA-induced MDA rise. Kidney form CsA treated rat showed marked vacuolar degeneration of tubular epithelium with excess of microcalcification. Severity of the lesions was markedly reduced in rats treated with PTX plus CsA. The results indicate that PTX reduces CsA-induced renal toxicity in rats.     

Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity

To evaluate the effect of Y-24180, a potent and long-acting antagonist to platelet-activating factor (PAF) receptors, on cyclosporine A (CsA)-induced acute renal failure, the influence of its pretreatment on the CsA-induced alterations in renal hemodynamics was examined in male Wistar rats under anesthesia. CsA decreased the clearances of inulin and p-aminohippuric acid (PAH) in a dose-dependent manner. Y-24180 (3 mg/kg, i.v.) tended to attenuate the CsA-induced reduction in inulin clearance. Y-24180 (0.3 and 3 mg/kg) significantly prevented the reductions in PAH clearance and the increase in calculated renal vascular resistance (RVR) in a dose-dependent manner. Serum endothelin-1 (Et) concentration in the CsA-treated group was higher than that in the vehicle-treated group. Y-24180 did not influence such the elevated Et concentration. Serum thromboxane B2 (TxB2) concentration did not increase by treatment with CsA. A significant correlation was observed between RVR and Et, but not TxB2 concentration. The present study showed that a PAF receptor antagonist, Y-24180, has the preventive effect against CsA-induced acute renal failure, which indicates that PAF may partly be involved in the mechanism of renal vasoconstriction induced by CsA. The present findings also support the idea that Et contributes to the CsA-induced acute nephrotoxicity.     

Effect of cyclosporin A on rat kidney catecholamines

The immunosuppressive agent, Cyclosporin A, (CsA) has been associated with nephrotoxicity and hypertension. The mechanism for these effects are not known. We therefore determined the levels of the catecholamines; epinephrine (EPI), norepinephrine (NE) and dopamine (DA) and some of their metabolites; epinine, dihydroxyphenyl-acetic acid (DOPAC), homovanillic acid (HVA), metanephrine (ME) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the kidneys of rats treated intraperitoneally with either CsA (120 micrograms/kg/body wt/day) or control vehicle (1 ml olive oil/kg body wt/day). Six control or CsA treated rats were sacrificed at 1 hour or 24 hours after a single treatment or after 7 days of daily treatment. Renal catecholamine levels were determined using HPLC-amperometric detector. Treatment with CsA increased renal NE and EPI levels by 59% and 70% respectively within 1 hour. In the rats sacrificed 24 hours after treatment, renal NE, EPI and DA levels were similar to or less than the control levels. Treatment with CsA for 7 days resulted in marginal increases in renal NE (22%) and EPI (30%). These changes were associated with a significant decrease in the levels of catecholamine metabolites in the CsA treated kidneys as compared to the controls. The above findings suggest that increases in renal catecholamines may be involved in the CsA-induced hypertension and nephrotoxicity, perhaps by increasing renovascular resistance.     

ACTH stimulation of adrenal epinephrine and norepinephrine release

Epinephrine (E) and norepinephrine (NE) levels were measured simultaneously in the adrenal veins of 6 patients before and after stimulation with 0.25 mg beta 1-24 ACTH. In 1 patient with Cushing's syndrome, E and NE were also measured before and 30 min after dexamethasone. There was a significant increase in NE and E secretion (p less than 0.002) from both adrenal glands after ACTH stimulation. In the patient with Cushing's syndrome, there was also a slight increase in plasma E levels after dexamethasone. It is postulated that ACTH stimulated NE and E secretion by augmenting blood flow through the adrenals and by induction of tyrosine hydroxylase and dopamine beta-hydroxylase, although a direct effect of ACTH on NE and E secretion cannot be excluded. It is also possible that the increase in adrenal catecholamine secretion after ACTH may be due to ACTH augmentation of catecholamine secretion by endogenous opioids such as beta-endorphin.     

Prednisolone suppresses cyclosporin A-induced apoptosis but not cell cycle arrest in MDCK cells

Cyclosporin A (CsA) is a potent immunosuppressive agent, and can cause severe adverse effects including nephrotoxicity partly due to generation of reactive oxygen species (ROS). Glucocorticoids, which are widely used in combination with CsA, have been shown to reduce oxidative injuries in various cells, but its mechanism is not understood well. To investigate the effects of prednisolone (Pd) on CsA-induced cellular damage and ROS generation in Madin-Darby canine kidney (MDCK) tubular epithelial cells, cells were treated with CsA, CsA plus Pd, or CsA plus vitamin E. Pretreatment with Pd protected cells from CsA-induced apoptosis but not from G(0)/G(1) cell cycle arrest even at its maximal protective concentration (30 microM), whereas vitamin E almost completely inhibited both CsA-induced apoptosis and cell cycle arrest at 1 microM concentration. In addition, Pd reduced the amount of CsA-induced ROS and showed partly restored catalase which was down-regulated by 10 microM CsA at both the mRNA and protein levels. Vitamin E completely abolished CsA-induced ROS generation and catalase attenuation at 10 microM concentration. Finally, the effects of 1 microM vitamin E on CsA-induced ROS and apoptosis as well as cell cycle arrest were similar to those of 30 microM Pd. We conclude that, in MDCK cells, Pd protects against CsA-induced cytotoxicity by suppressing ROS generation, although its protective effect is weaker than that of vitamin E.     

Vascular changes in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet.

Functional and morphological changes of blood vessels in cyclosporine A (CsA)-induced hypertension and nephrotoxicity were studied in spontaneously hypertensive rats (SHR). The role of the L-arginine-nitric oxide (NO) pathway and the importance of oxidative stress in CsA toxicity were also assessed. SHR (7-8 week old) on a high-sodium diet were treated with CsA (5 mg kg(-1) d(-1) s.c.) for 6 weeks. A proportion of the rats were treated concomitantly with the NO precursor L-arginine (1.7 g kg(-1)d(-1) p.o.). CsA elevated blood pressure and caused renal dysfunction and morphological nephrotoxicity. CsA also impaired mesenteric and renal arterial function and caused structural damage to intrarenal and extrarenal small arteries and arterioles. Medial atrophy of the mesenteric resistance vessels and decreased viability of smooth muscle cells of the thoracic aorta were observed. Renal and arterial damage was associated with the presence of inflammatory cells. CsA did not affect markers of the L-arginine-NO pathway (urinary cyclic GMP excretion or endothelial or inducible NO synthase expression in kidney, aorta or heart) or oxidative stress (urinary excretion of 8-isoprostaglandin F2alpha, plasma urate concentration or total radical trapping capacity). Concomitant L-arginine treatment did not affect CsA-induced changes in blood pressure or histological findings but tended to alleviate the arterial dysfunction. The renal and cardiovascular toxicity of CsA was associated with arterial dysfunction and morphological changes in small arteries and arterioles in SHR on a high-sodium diet. The findings did not support the role of oxidative stress or a defect in the L-arginine-NO pathway.     

Human Adipose Tissue Derived Mesenchymal Stem Cells Aggravate Chronic Cyclosporin Nephrotoxicity by the Induction of Oxidative Stress

The aim of this study was to investigate whether hATMSCs protect against cyclosporine (CsA)-induced renal injury. CsA (7.5 mg/kg) and hATMSCs (3×10⁶/5 mL) were administered alone and together to rats for 4 weeks. The effect of hATMSCs on CsA-induced renal injury was evaluated by assessing renal function, interstitial fibrosis, infiltration of inflammatory cells, and apoptotic cell death. Four weeks of CsA-treatment produced typical chronic CsA-nephropathy. Combined treatment with CsA and hATMSCs did not prevent these effects and showed a trend toward further renal deterioration. To evaluate why hATMSCs aggravated CsA-induced renal injury, we measured oxidative stress, a major mechanism of CsA-induced renal injury. Both urine and serum 8-hydroxydeoxyguanosine(8-OHdG) levels were higher in the CsA+hATMSCs group than in the CsA group (P<0.05). An in vitro study showed similar results. Although the rate of apoptosis did not differ significantly between HK-2 cells cultured in hATMSCs-conditioned medium and those cultured in DMEM, addition of CsA resulted in greater apoptosis in HK-2 cells cultured in hATMSCs-conditioned medium. Addition of CsA increased oxidative stress in the hATMSCs-conditioned medium. The results of our study suggest that treatment with hATMSCs may aggravate CsA-induced renal injury because hATMSCs cause oxidative stress in the presence of CsA.     

Prevention by alpha and beta adrenoreceptor agonists and lithium hydroxybutyrate of injuries to the endothelium of the rabbit aorta induced by catecholamines

The damage of endothelial cells and intercellular junctions caused by 10 microM epinephrine (E) and 10 microM norepinephrine (NE) has been observed in perfused rabbit aorta. Simultaneous perfusion of the rabbit aorta with E and NE induced marked endothelial injuries at very low drug doses (0.1 microM). Alpha- and beta-adrenoceptor antagonists prevented the development of catecholamine-induced endothelial alterations. Lithium hydroxybutyrate partially prevented endothelial alterations caused by 10 microM epinephrine, but blocked completely morphological injuries caused by simultaneous perfusion of the rabbit aorta with 0.1 microM E and NE.     

Role of Ca2+-activated Cl- channels in the mechanism of apoptosis induced by cyclosporin A in a human hepatoma cell line

The mechanism of apoptosis induced by cyclosporin A (CsA) in a human hepatoma cell line was investigated. CsA induced apoptosis in a dose- and time-dependent manner in HepG2 human hepatoma cells. CsA induced Cl- efflux, which was significantly blocked by niflumic acid (NA), a specific inhibitor, and flufenamic acid (FA), 5-nitro-2-(3-phenyl-propylamino)-benzoate (NPPB), and 4,4'-diisothiocyanoto-stibene-2,2'-disulfonic acid (DIDS), non-specific inhibitors of Ca2+-activated Cl- channels (CaCCs), not by calyculin A, an inhibitor of K+,Cl- -cotransport. In addition, CsA did not alter intracellular K+ concentration. Moreover, CsA increased intracellular Ca2+ concentration, and treatment with BAPTA/AM, an intracellular Ca2+ chelator, significantly inhibited the CsA-induced Cl- efflux, indicating that CsA induced Cl- efflux through the activation of CaCCs. Treatment with these CaCC inhibitors (NA, FA, NPPB, and DIDS) markedly prevented the CsA-induced apoptosis. Taken together, these results suggest that CaCCs may mediate apoptosis induced by CsA in HepG2 cells. Furthermore, these results provide a new insight into the novel function of CaCCs in the regulation of cancer cell apoptosis associated with perturbation of intracellular Ca2+ signal.     

Cyclosporine A-induced acute hepatotoxicity in guinea pigs is associated with endothelin-mediated decrease in local hepatic blood flow

AimsTo bring further insight into the mechanism of cyclosporine A (CsA)-induced hepatotoxicity, the acute effect of CsA on local hepatic blood flow (LHBF) and its association with systemic hemodynamics, histopathological and biochemical indicators of liver toxicity were studied in guinea pigs in vivo. The association of endothelin (ET) and/or Cremophor-EL (C-EL, vehicle in parenteral CsA preparation) with CsA effects was also investigated.Main methodsAnimals were assigned into five groups; control, CsA, C-EL, Bosentan (non-selective ET receptor antagonist) + CsA, and BQ-123 (ET_A receptor antagonist) + CsA. CsA was infused intravenously (i.v.) at 20 and 10 mg/kg doses by 15 min interval. Antagonists were administered 15 min before CsA infusion. LHBF and mean arterial blood pressure (MAP) changes were simultaneously recorded. Blood and liver samples were collected for biochemical and histopathological examinations.Key findingsCsA, but not C-EL, decreased LHBF by 53.3% at the end of 30 min. Although being non-significant, CsA slightly increased MAP suggesting that, CsA-induced acute decrease in LHBF was likely independent of MAP changes. Bosentan (5 mg/kg, i.v.) and BQ-123 (1 mg/kg, i.v.) pre-treatments prevented the CsA-induced decrease in LHBF suggesting that CsA decreases LHBF through an ET-related mechanism. Additionally, CsA, but not its vehicle C-EL, caused marked acute pathological changes in the liver morphology.SignificanceCsA-induced findings of acute hepatotoxicity were prevented by bosentan and BQ-123 pre-treatments. Thus, CsA seems to exert acute hepatotoxic effect through ET-related mechanisms.     

Provinol prevents CsA-induced nephrotoxicity by reducing reactive oxygen species, iNOS, and NF-kB expression.

Cyclosporine A (CsA) use is associated with several side effects, the most important of which is nephrotoxicity that includes, as we previously showed, tubular injury and interstitial fibrosis. Recently, many researchers have been interested in minimizing these effects by pharmacological interventions. To do this, we tested whether the administration of a red wine polyphenol, Provinol (PV), prevents the development of CsA-induced nephrotoxicity. Rats were treated for 21 days and divided into four groups: control; group treated with PV (40 mg/kg/day by oral administration in tap water); group treated with CsA (15 mg/kg/day by subcutaneous injection); group treated with CsA plus PV. CsA produced a significant increase of systolic blood pressure; it did not affect urinary output, but caused a significant decrease in creatinine clearance. These side effects were associated with an increase in conjugated dienes, which are lipid peroxidation products, inducible NO-synthase (iNOS), and nuclear factor (NF)-kB, which are involved in antioxidant damage. However, PV prevented these negative effects through a protective mechanism that involved reduction of both oxidative stress and increased iNOS and NF-kB expression induced by CsA. These results provide a pharmacological basis for the beneficial effects of plant-derived polyphenols against CsA-induced renal damage associated with CsA.     

Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats

Calcineurin has recently been implicated as a mediator in the signaling pathways that transform intracellular calcium signals to the phenotype of myocardial hypertrophy. The present study was conducted to examine the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on myocardial hypertrophy and remodeling during congestive heart failure (CHF) in rats. After ligation of the left coronary artery, rats were randomized to treatment with CsA or vehicle for 14 days. Compared with vehicle, CsA substantially attenuated myocardial hypertrophy in the CHF rats as assessed by alterations in ventricular weight-to-tibial length ratios (P < 0.05). Myocardial gene expression of skeletal alpha-actin was also reduced in the failing left ventricle (LV) after treatment with CsA (P < 0. 05), although the mRNA levels were still substantially elevated relative to those of sham rats. CsA-induced inhibition of compensatory myocardial hypertrophy in the CHF rats led to increased dilatation of the LV cavity and reduced fractional shortening and peak positive and negative first derivatives of LV pressure (P < 0. 05). Plasma renin and endothelin-1 levels were increased in the CHF-CsA rats, providing humoral cues of aggravated cardiac function. Thus this study supports a crucial role of calcineurin-dependent pathways in the mechanisms of compensatory myocardial hypertrophy during CHF. In addition, our data indicate that inhibition of compensatory myocardial hypertrophy exerts detrimental effects on cardiac remodeling and function after myocardial infarction.     

Cyclosporin A, an Immunosuppressive Drug, Induces Programmed Cell Death in Rat C6 Glioma Cells by a Mechanism that Involves the AP-1 Transcription Factor

Abstract: Cyclosporin A (CsA) is a clinically important immunosuppressive drug widely used to prevent graft rejection following organ or bone marrow transplantation. Although there are reports of serious neurologic alterations associated with the use of the drug, the precise mechanism of its action on the CNS still remains unknown. We studied the effects of CsA on the growth of C6 glioma cells. We found that CsA inhibits the growth of C6 glioma cells in a dose-dependent manner and induces morphological changes such as shrinkage of the cell body and loss of extensions followed by cell death. The analysis of DNA from CsA-treated cells revealed a ladder-like pattern of fragmented DNA. Acridine orange staining showed the occurrence of apoptotic changes in nuclear morphology. Apoptotic morphological alterations were prevented by the treatment with cycloheximide. Altogether, our findings suggest that the CsA-induced cell death of C6 glioma cells bears all the features characteristic of programmed cell death. We also observed a significant increase in the DNA-binding activity of AP-1 during CsA-induced apoptosis. The AP-1 induction preceded the appearance of apoptotic, morphological changes and was accounted for by an increase in the expression of c-Jun protein. The occurrence of increased levels of AP-1 complex and c-Jun protein during CsA-induced programmed cell death suggests its involvement in the induction of apoptosis.     

Effect of simvastatin on remodeling of the left ventricle and aorta in L-NAME-induced hypertension

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to prevent or reverse hypertrophy of the LV in several models of left ventricular hypertrophy. The aim of the present study was to determine whether treatment with simvastatin can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) remodeling in NG-nitro-L-arginine methyl ester(L-NAME)-induced hypertension. Four groups of rats were investigated: control, simvastatin (10 mg/kg), L-NAME (40 mg/kg) and L-NAME + simvastatin (in corresponding doses). Animals were sacrificed and studied after 6 weeks of treatment. The decrease of NO-synthase activity in the LV, kidney and brain was associated with hypertension, LV hypertrophy and fibrosis development and remodeling of the aorta in the L-NAME group. Simvastatin attenuated the inhibition of NO-synthase activity in kidney and brain, partly prevented hypertension development and reduced the concentration of coenzyme Q in the LV. Nevertheless, myocardial hypertrophy, fibrosis and enhancement of DNA concentration in the LV, and remodeling of the aorta were not prevented by simultaneous simvastatin treatment in the L-NAME treated animals.We conclude that the HMG-CoA reductase inhibitor simvastatin improved nitric oxide production and partially prevented hypertension development, without preventing remodeling of the left ventricle and aorta in NO-deficient hypertension.     

17beta-estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats

Estrogens have been implicated in both worsening and protecting from cardiovascular disease. The effects of 17beta-estradiol (E2) on the cardiovascular system may be mediated, at least in part, by its modulation of local tissue renin-angiotensin systems (RAS). We assessed two critical components, angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT(1)R), in the heart, lung, abdominal aorta, adrenal, kidney, and brain in four groups of female Wistar rats (n = 5-6/group): 1) sham ovariectomized, 2) ovariectomized (OVX) treated with subcutaneous vehicle, 3) OVX treated with 25 mug/day (regular) E2 subcutaneously, and 4) OVX treated with 250 mug/day (high) subcutaneous E2 for 2 or 5 wk. After 2 wk, plasma ACE activity was not altered by OVX, but it was 34-38% lower in OVX + regular E2 and OVX + high E2 rats compared with sham OVX rats, and these decreases were no longer present after 5 wk. After 5 wk, OVX alone increased ACE activity and binding densities, and AT(1)R binding densities by 15-100% in right ventricle, left ventricle (LV), kidney, lung, abdominal aorta, adrenal and several cardiovascular regulatory nuclei in the brain. These effects were, for the most part, prevented by regular E2 replacement and were reversed to decreases by high E2 treatment. This regulation of tissue ACE and AT(1)R is significant as the activity of these tissue RAS contributes to the pathogenesis and/or progression of hypertension, atherosclerosis, and LV remodeling after myocardial infarction.     

Reproducibility of plasma catecholamine concentrations at rest and during exercise in man

The purpose of this study was to test the reproducibility of plasma norepinephrine (NE) and epinephrine (E) concentrations, at rest and during exercise, in man. Twelve young men were evaluated on two occasions (one week apart) at rest in supine and sitting positions and during dynamic exercise on bicycle ergometer: 5 min at a low intensity workload (heart rate = 131-133 bt min-1) and 5 and 20 min at a higher intensity (174-175 bt min-1). Mean plasma NE and E concentrations were not significantly different (p less than 0.05) on the two occasions in any of the experimental situations. However large within-subject variations were present, and the "standard errors of a single measurement" corrected for the variability of the catecholamine assay, ranged from 14 to 50% for NE and 14 to 37% for E. These results indicate that the mean plasma NE and E concentrations observed in a group of subjects are reproducible from one week to the other, but that individual plasma NE and E concentrations are not. This lack of reliability of a single determination of plasma catecholamine concentrations might be due to cyclic variations of plasma NE and E concentrations over time.     

Influence of photoperiods on glycemic and adrenal catecholaminergic responses to melatonin administrations in adult male roseringed parakeets, Psittacula krameri Neumann

Effects of daily (one hour prior to onset of darkness) injection of melatonin (25 micrograms/100 g body wt. for 30 days) on concentrations of blood glucose and adrenal catecholamines were studied in adult male roseringed parakeets, P. krameri under both natural (NP; about 12L:12D) and artificial long (LP; 16L:8D; lights were available in between 0600 and 2200 hrs) or short (SP; 8L:16D; lights were available between 0600 and 1400 hrs) photoperiodic conditions. The results indicate that neither LP, nor SP as such exerts any significant effect on blood glucose titre of control (vehicle of hormone administered) birds. Treatment with melatonin, however, induced hyperglycemia in both NP and LP bird groups, but hypoglycemia in SP birds. Unlike glycemic levels, amount of epinephrine (E) and norepinephrine (NE) in adrenals of control birds exhibited significant changes under altered photoperiods. A decrease in E and an increase in NE were noted in adrenals of both LP and SP birds. Exogenous melatonin in NP birds also caused a decrease in E and concomittant rise in NE levels. On the other hand, treatment of melatonin in both LP and SP bird groups resulted in an increase in the quantity of both E and NE compared to respective values in adrenals of melatonin injected NP birds. However, relative to the amount of E and NE in adrenals of placebo treated LP and SP birds, significant effect of melatonin treatment was observed only in SP birds. The results suggest that influences of exogenous melatonin on the levels of both blood glucose and adrenal catecholamines are largely modulated by short rather than long photoperiods.     

Melatonin Prevents Cyclosporine-induced Nephrotoxicity in Isolated and Perfused Rat Kidney

Cyclosporine A (CsA) is a potent and effective immunosuppressive agent, but its action is frequently accompanied by severe renal toxicity. The precise mechanism by which CsA causes renal injury is not known. Reactive oxygen species (ROS) have been shown to play a role, since CsA-induced renal lipid peroxidation is attenuated in vivo and in vitro by the concomitant administration of antioxidants such as vitamin E. We show here the effect of the antioxidant melatonin (MLT), a hormone produced by the pineal gland during the dark phase of the circadian cycle, in a model of CsA nephrotoxicity in the isolated and perfused rat kidney. Kidneys isolated from rats were divided into seven groups. At the end of perfusion, malondialdehyde and 4-hydroxyalkenals (MDA+4-HDA), metabolites of nitric oxide N O 2 &#109 +N O 3 &#109 were measured and histopathological examination was performed. CsA treatment induced a significant increase in MDA+4-HDA while not affecting the nitric oxide metabolite level. MLT remarkably prevented glomerular collapse and tubular damage as revealed by morphometric analysis. Our study suggests that lipid peroxidation is an early important event in the pathogenesis of CsA nephrotoxicity and that MLT is able to protect kidneys from CsA at a relatively low concentration.     

Melatonin prevents cyclosporine-induced nephrotoxicity in isolated and perfused rat kidney

Cyclosporine A (CsA) is a potent and effective immunosuppressive agent, but its action is frequently accompanied by severe renal toxicity. The precise mechanism by which CsA causes renal injury is not known. Reactive oxygen species (ROS) have been shown to play a role, since CsA-induced renal lipid peroxidation is attenuated in vivo and in vitro by the concomitant administration of antioxidants such as vitamin E. We show here the effect of the antioxidant melatonin (MLT), a hormone produced by the pineal gland during the dark phase of the circadian cycle, in a model of CsA nephrotoxicity in the isolated and perfused rat kidney. Kidneys isolated from rats were divided into seven groups. At the end of perfusion, malondialdehyde and 4-hydroxyalkenals (MDA+4-HDA), metabolites of nitric oxide N O 2 - +N O 3 - were measured and histopathological examination was performed. CsA treatment induced a significant increase in MDA+4-HDA while not affecting the nitric oxide metabolite level. MLT remarkably prevented glomerular collapse and tubular damage as revealed by morphometric analysis. Our study suggests that lipid peroxidation is an early important event in the pathogenesis of CsA nephrotoxicity and that MLT is able to protect kidneys from CsA at a relatively low concentration.