Aluminum exacerbates cyclosporin induced nephrotoxicity in rats

Cyclosporin (CSA) has been universally used as an immunosuppressant for the management of allotransplantation and autoimmune diseases. However, nephrotoxicity of CSA limits its use to optimum level. Aluminum (Al) is an extensively distributed element in the environment and human exposure to this metal is unavoidable. Recent studies suggest that even a slight impairment of renal function may increase the Al body burden significantly, which may lead to neurotoxicity, nephrotoxicity, osteodystrophy or hypochromic anemia. In the present study, an attempt was made to study the effect of concomitant use of Al and CSA on structure and function of kidney in rats. This study was undertaken in two steps. In the first set of experiments, the effect of single dose of Al (1% Al2(SO4)3 18H2O) on the nephrotoxicity of multiple doses of CSA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) was studied, where as in the second set of experiments the effect of multiple doses of Al (0.25%, 0.5% and 1%) on single dose of CSA (50 mg/kg) was undertaken. Male Sprague-Dawley rats (weighing 230 +/- 20 g) were used in this study. CSA was given once a day by gavage for seven days, where as Al was given in drinking water for the same period. Twenty four hours after the last dose of CSA, animals were sacrificed and blood and kidney were collected for biochemical and histopathological studies. The bio-chemical parameters included blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Al levels. The kidney homogenates were assayed for malondialdehyde (MDA) and lipid hydroperoxides (LPH). Treatment of rats with CSA alone produced dose-dependent structural and functional changes in kidney. Although Al alone failed to produce any deleterious effect on renal function, it significantly increased the bioavailability and nephrotoxicity of CSA. Al also exacerbated CSA induced increase in oxidative stress (as evident by increased MDA and LPH). Thus, the exacerbation of CSA nephrotoxicity by Al may be attributed to increased bioavailability of CSA and excessive generation of free radicals following concomitant use of these drugs.     

Mercury exacerbates cyclosporin nephrotoxicity in rats

Background The use of cyclosporin (CsA) in the presence of other nephrotoxic drugs poses a great challenge to physicians. This study was designed to address the effect of concomitant administration of mercury and cyclosporin on nephrotoxicity of rats. Methods Male Sprague-Dawley rats (weighing 230±20 g) were divided into the following 8 groups of 7 animals each: group 1, control; group 2, mercury alone; group 3, cyclosporin 12.5 mg/kg; group 4, cyclosporin 25 mg/kg; group 5, CsA 50 mg/kg; group 6, CsA 12.5 mg/kg+mercury; group 7, CsA 25 mg/kg+mercury; and group 8, CsA 50 mg/kg+mercury. Mercury (1 mg/kg) was given by subcutaneous injection, and CsA, by oral gavage; drugs were given once a day for 7 days. Twenty-four hours after the last dose of drugs, the animals were killed, and blood samples were assayed for BUN, serum creatinine, and CsA levels. The left kidney was analyzed for malondialdehyde, lipid hydroperoxides, vitamin E, and glutathione levels, and histopathologic analysis was done on the right kidney. Results Mercury significantly exacerbated CsA-induced nephrotoxicity. There was a highly significant increase in oxidative stress in animals treated with the combination of CsA and mercury. Mercury also increased the bioavailability of CsA in rats. Conclusions Concomitant treatment of mercury with CsA produced severe nephrotoxicity. The enhanced nephrotoxicity may be attributed to the increased bioavailability of CsA and an increase in lipid peroxidation after concomitant use of these drugs.     

Studies on nephrotoxicity of cyclosporin. 1. Nephrotoxicity in rats receiving cyclosporin

Cyclosporin (CS) is a potent immunosuppressant that has been used in organ transplantation, but it has a serious nephrotoxic effect. To investigate its effects on renal function and structure, we carried out biochemical and morphological examinations in rats. Male Wistar rats each weighing 250 g were used. Rats were given various dose regimens (100, 50, 25 and 10 mg/kg/day) of CS orally over a 21-day period. All the rats were killed and examined on the 22nd day. Blood urea nitrogen (BUN), serum and urinary creatinine and urinary N-acetyl-s-D-glucosaminidase (NAG) were measured before administration and on the 7th, 14th and 21st day after administration. Kidneys were examined with light and electron microscopes. All rats that had received 100 mg/kg/day CS died within 12 days after a severe loss in body weight. Rats that had received 50 or 25 mg/kg/day CS had lost weight which never returned to the weight before administration. A high CS dose caused a significant elevation of BUN unaccompanied by a corresponding rise in serum creatinine. Reduction of creatinine clearance was not prominent during the experimental course. Although the urinary NAG activity was increased in high dose groups, the elevation was not related to dose. Morphological alterations were confined to the proximal tubuli and they consisted of tubular cell vacuolation and increased number of lysosomes. However, these alterations were mild and not related to the CS dose.     

Studies on nephrotoxicity of cyclosporin. II. Nephrotoxicity in rats receiving cyclosporin and sulfamethoxazole-trimethoprim

A cyclosporin (CS) has a serious nephrotoxic effect which is synergistic with sulfamethoxazole-trimethoprim (ST) on renal allograft recipients. The effects of CS and ST on renal function and structure, were examined biochemically and morphologically in rats. Male Wistar rats each weighing 250 g were given various dose regimens (CS 50 mg/kg + ST 600 mg/kg, CS 25 mg/kg + ST 600 mg/kg, CS 10 mg/kg + ST 600 mg/kg) orally for 21 days, and were killed and examined on the 22nd day. Blood urea nitrogen (BUN), serum and urinary creatinine, and urinary N-acetyl-s-D-glucosaminidase (NAG) were measured before administration and on the 7th, 14th and 21st day after administration. The serum levels of CS, sulfamethoxazole (SMX) and trimethoprim (TMP) were measured on the 21st day after administration. Kidneys were examined by light and electron microscopy. All rats that had received 50 mg/kg CS and 600 mg/kg ST died within 9 days after a severe loss in body weight. Rats that had received 25 mg/kg CS and 600 mg/kg ST had lost weight. A high dose CS and ST caused a significant elevation of BUN. The level of serum creatinine was significantly elevated only in rats that had received 25 mg/kg CS and 600 mg/kg ST. Decrease in creatinine clearance was not significant and the urinary NAG activity was not altered significantly during the experimental course. Morphological alterations were confined to the proximal tubuli and they consisted of PAS positive globules, loss of nuclei, tubular cell vacuolation and increased number of lysosomes. However, these alterations were mild and not related to the dose of CS and ST.(ABSTRACT TRUNCATED AT 250 WORDS)     

转化生长因子-β1反义寡核苷酸减轻环孢素A对大鼠的慢性肾毒性

目的以阳离子脂质体介导的转化生长因子-β1(TGF-β1)反义寡核苷酸(AODN)阻止TGF-β1的表达,观察其对大鼠使用环孢素A(CsA)后慢性肾毒性的防治作用。方法低盐饮食条件下,给SD雄性大鼠腹腔注射CsA 15 mg·kg-1·d-1,持续28 d;另两组在腹腔注射CsA的同时,于第15、20 d分别予以TGF-β1硫代磷酸AODN和阳离子脂质体包裹的TGF-β1硫代磷酸AODN尾静脉注射。检测各组血清肌酐的改变,组织形态学的变化;免疫组织化学法及聚合酶链式反应(RT- PCR)检测TGF-β1蛋白及其mRNA在组织的表达。结果成功地模拟了CsA对大鼠慢性肾毒性的病理改变。阳离子脂质体介导的TGF-β1硫代磷酸AODN可以显著抑制TGF-β1的表达,减轻CsA 所致慢性肾毒性的病理改变,并能改善肾功能。结论阳离子脂质体介导的TGF-β1硫代磷酸AODN通过抑制TGF-β1的表达,有效防治CsA对大鼠的慢性肾毒性。     

Low-dose cyclosporin nephrotoxicity in the rat

The nephrotoxicity of cyclosporin (CsA) continues to be a clinicalproblem that detracts from its obvious benefits as an immunosuppressiveagent. Animal models designed to study the problem have generallyrelied either on chronic administration of high doses of thedrug or acute administration of single i.v. doses. The presentstudy establishes a model of CsA nephrotoxicity using dosesof the drug comparable to those used in man administered overa time period sufficient for haemodynamic and structural changesto become evident. The technique used measures glomerular filtration rate (GFR)and effective renal plasma flow (ERPF) by the plasma clearanceof chromium EDTA and iodohippuran respectively. This has theadvantage of allowing sequential measurements in individualanimals. Significant impairment of GFR was seen in animals treated intraperitoneallywith doses of CsA as low as 5 mg/kg/day. CsA 7.5 mg/kg/day causeda significant reduction in ERPF, and at 10 mg/kg/day and greaterfiltration fraction also declined significantly. Detailed histologicalexamination of the kidneys from these animals also revealedsignificant tubular dilatation at 10 mg/kg/day and above. This model of CsA toxicity circumvents many of the problemsassociated with other models. The animals can be studied longitudinallyand the period of administration has relevance to clinic practice.This work provides the basis for further studies which can closelymimic the clinical situation using doses similar to those usedfor human maintenance immunosuppression.     

Influence of enalapril on experimental cyclosporin A nephrotoxicity

. The purpose of this study was to investigate if enalapril could be administered with cyclosporin A (CyA) to reduce its nephrotoxicity. Sixty rats were divided into five groups: group I, Control group; group II, rats treated with oral enalapril; group III, rats treated with CyA; group IV, rats treated with CyA and enalapril; group V, rats treated with enalapril before the CyA therapy. At the end of the therapy mean serum creatinine concentrations were not statistically different between the groups (P>0.05), in groups treated with CyA there were no statistically significant differences between mean CyA levels (P>0.05), and mean blood urea nitrogen levels of the groups treated with CyA were significantly elevated (P<0.05) compared with groups not treated with CyA. Morphologically acute CyA nephrotoxicity was evaluated by the following features: (1) tubular vacuolization, (2) tubular necrosis, (3) tubular microcalcification, and (4) peritubular capillary congestion. These lesions were scored semiquantitatively on a scale from 0 to 4+. The most common tubular pathology was tubular vacuolization, which was more severe in groups III and IV. Tubular necrosis was most severe in group III. In conclusion, enalapril seems to suppress the severest form of CyA nephrotoxicity, namely tubular necrosis, if administered prior to CyA treatment. Received May 2, 1995; received in revised form September 22, 1995; accepted January 5, 1996     

Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats

BACKGROUND: Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats. METHODS: Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats. RESULTS: CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality. CONCLUSIONS: MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.     

Chronic irreversible nephrotoxicity from cyclosporin A

A 43-year-old woman developed progressive renal insufficiency while receiving cyclosporin A after live donor kidney transplantation. Despite the discontinuation of this drug and substitution with azathioprine, the renal function continued to deteriorate leading to eventual graft loss. The other causes of chronic renal failure such as allograft rejection, recurrent or 'de novo' glomerulonephritis or obstructive uropathy were not evident. There is a high frequency of acute reversible nephrotoxicity from cyclosporin A, but this patient's clinical course suggests that chronic irreversible renal failure can also occur in patients receiving this drug.     

Cellular and molecular mechanisms of cyclosporin nephrotoxicity

Cyclosporin therapy is associated with several forms of nephrotoxicity, the most significant of which are reversible impairment of glomerular filtration and irreversible interstitial fibrosis. Impaired glomerular filtration is due to both reduction in Kf, the glomerular capillary ultrafiltration coefficient, and to reduction in renal blood flow. The mechanisms responsible for the low Kf are not well defined, but heightened mesangial cell contractility may contribute. Reduced renal blood flow with chronic cyclosporin therapy arises from both endothelial damage and altered eicosanoid metabolism, in particular increased thromboxane synthesis. Renal interstitial fibrosis, which develops in some patients after approximately 6-12 months of cyclosporin therapy, poses a major limitation to the chronic use of the drug. Two mechanisms likely contribute to cyclosporin-associated interstitial fibrosis. First, endothelial injury and vasoconstriction produce renal ischemia, which in turn is associated with enhanced synthesis of extracellular matrix proteins. Second, cyclosporin likely influences the accumulation of matrix proteins in the renal interstitium through nonhemodynamic mechanisms, as suggested by altered matrix accumulation in non-renal tissues. This effect of cyclosporin may be direct or indirect, via mediators including cytokines, peptide growth factors, and thromboxane. The molecular mechanisms of cyclosporin action on immunologic and mesenchymal cells are active areas of investigation. Intracellular targets of cyclosporin include mitochondrial respiration, cellular calcium signaling, protein kinase C, protein synthesis, and peptidyl-prolyl isomerases. However, the significance of these intracellular effects for cyclosporin nephrotoxicity remains to be demonstrated.     

Ameliorative potential of gemfibrozil and silymarin on experimentally induced nephrotoxicity in rats

IntroductionAcute nephrotoxicity is a frequent complication of critical illness especially in the inpatient setting. Cisplatin is one of the most active anticancer drugs. Nephrotoxicity is the most common side effect associated with cisplatin treatment. Silymarin is widely used for hepatic disorders due to its antioxidant and anti-inflammatory properties. Gemfibrozil, a hypolipidemic drug, has also antioxidant and anti-inflammatory properties.ObjectiveTo detect the effect of gemfibrozil and silymarin either alone or in combination on cisplatin-induced nephrotoxicity in rats.Subjects and methodsFifty albino rats were divided into 5 equal groups: Control untreated group, cisplatin treated group, gemfibrozil + cisplatin treated group, silymarin + cisplatin treated group, gemfibrozil + silymarin + cisplatin treated group. Blood urea, serum creatinine, creatinine clearance, urinary N-acetyl beta-d-glucosaminidase, urinary protein, tissue superoxide dismutase, malondialdehyde, reduced glutathione, tumour necrosis factor alpha and mitochondrial complex I activity were determined. Kidneys were excised for histopathological examination.ResultsGemfibrozil and/or silymarin efficiently attenuated cisplatin-induced nephrotoxicity evidenced by significant decrease in blood urea, serum creatinine, urinary N-acetyl beta-d-glucosaminidase, urinary protein, tissue malondialdehyde and tissue tumour necrosis factor alpha with significant increase in creatinine clearance, tissue reduced glutathione, tissue superoxide dismutase and mitochondrial complex I activity simultaneous with reduction of the necrotic damage and progressively increasing apoptotic index assessed by renal histopathological examination compared to the cisplatin treated group.ConclusionThe combination of gemfibrozil and silymarin has protective effects against cisplatin-induced nephrotoxicity in rats better than each of these drugs alone due to anti-inflammatory and antioxidant properties of the used drugs.     

High-turnover osteoporosis is induced by cyclosporin A in rats

Cyclosporin A (CsA) is used widely as an immunosuppressive agent, but it induces osteoporosis as a prominent side effect. To elucidate the mechanisms involved in CsA-induced osteoporosis, the effects of CsA on bone metabolism were investigated in a rat experimental model. Fifteen-day-old rats were fed a powdered diet containing or lacking CsA for 8–30 days. Analysis was performed by micro-computed tomography (μCT) and light microscopy to examine histomorphometric changes in rat tibiae on days 8, 16, and 30. Plasma parathyroid hormone (PTH) and osteocalcin (OCN) levels were determined by enzyme-linked immunosorbent assay (ELISA) on days 8, 16, and 30. The expression of OCN, osteopontin (OPN), and cathepsin K mRNAs in tibial bone marrow was examined by Northern blot analysis on days 8 and 16. Although no significant differences were observed in tibial length during the experimental periods, or in histomorphometric parameters on day 8, an apparent decrease in bone volume was observed in the CsA-treated group after day 16. Histologic analysis showed that the number of osteoblasts and osteoclasts on the surface of trabecular bone in the CsA-treated group had increased significantly on day 16. Plasma PTH and OCN levels in CsA-treated rats were significantly higher than those in control animals on day 8. Northern blot analysis revealed that the CsA-treated group showed an increase in the expression of OCN, OPN, and cathepsin K mRNAs on day 8 compared with the controls. These findings suggest that bone resorption in CsA-treated rats is induced by high-turnover osteoporosis and that bone remodeling activity may be activated by PTH.     

雷帕霉素对环孢素A诱导的慢性肾毒性的影响

目的　了解雷帕霉素 (RPM)对环孢素A(CsA)诱导的慢性肾毒性的影响。方法　对进低盐饮食的大鼠给予RPM与CsA溶剂、RPM (0 .5mg·kg-1·d-1与 1mg·kg-1·d-1)、CsA (4mg·kg-1·d-1与 8mg·kg-1·d-1)以及两者联用 ,均用药 2 8d。结果　接受RPM 1mg·kg-1·d-1的大鼠血糖明显升高 ,加重CsA(4mg·kg-1·d-1)诱导的慢性肾毒性作用 ;而亚治疗剂量的RPM (0 .5mg·kg-1·d-1)与CsA(4mg·kg-1·d-1)联用只引起轻度的血糖上升及肾小管细胞受损与间质纤维化 ,与前者相比 ,P <0 .0 5。治疗剂量的RPM(1mg·kg-1·d-1)与CsA(8mg·kg-1·d-1)联用则导致更为显著的肾功能受损、结构改变与高糖血症。结论　亚治疗剂量的RPM与CsA的联用可协同产生慢性肾毒性作用     

Effect of cyclosporin on the thymus and spleen in rats

Cyclosporin is a potent immunosuppressive agent. When cyclosporin is administered at a dose of 5 mg/kg/day i.p. for 2 weeks and 8 weeks, 15 mg/kg/day i.p. for 2 weeks, and 30 mg/kg/day i.p. for 1 week to normal Fischer rats, all thymuses were atrophic and their weight and number of thymocytes decreased dose dependently. However, no change was observed in spleen size. Histologically, thymic medulla was severely atrophic and the cellularity of thymic cortex, and splenic periarterial sheath and splenic marginal zone were decreased. Thymic cortex was more atrophic in the high dose group. All components recovered to near normal morphology 2 to 3 weeks after drug withdrawal, but recovery of splenic change was delayed in many rats. A reduction of T lymphocytes, particularly, helper T lymphocytes was detected by avidin-biotin peroxidase complex method using the monoclonal antibodies, W3/13, W3/25, OX8 and OX6. Many of the rats administered cyclosporin developed infection. Because of these changes in the immune response, precaution must be taken to prevent infection.     

Effect of cyclosporin on generalized Shwartzman reaction in diabetic rats

The effect of cyclosporin (CsA) on the endotoxin-induced generalized Shwartzman reaction (GSR) was studied in diabetic and nondiabetic rats. After 4.5 wk of diabetes, CsA (20 mg/kg) or intralipid as a control substance was given intraperitoneally daily for 10 days. Next, diabetic rats were given either high-dose (2 mg/kg or low-dose (0.1 mg/kg) endotoxin (Escherichia coli 026:B6 lipopolysaccharide B) as a single injection. The rats were killed at intervals of 1, 4, 8, and 24 h. No significant glomerular thrombi were seen in the nondiabetic control animals, whereas the severity of glomerular thrombi in the diabetic animals was dependent on the presence or absence of CsA, endotoxin dose, and degree of glycemic control. In the diabetic rats, glomerular thrombi occurred maximally at 4 h but were no longer present at 24 h. The CsA/high-dose-endotoxin rats had fewer glomerular thrombi than rats receiving the intralipid/high-dose endotoxin, but this difference was not statistically significant. The CsA/low-dose-endotoxin rats had increased glomerular thrombi compared with the intralipid/low-dose-endotoxin rats (P less than 0.01). Insulin treatment reduced the glomerular capillary thrombi in the CsA/low-dose-endotoxin diabetic animals. Thus, CsA aggravates the GSR with low-dose endotoxin but has no significant effect when high-dose endotoxin is given. Improved glycemic control reduces the GSR in CsA-treated rats. Thus, the interrelationships of diabetes, endotoxin, and CsA on the GSR are complex, and the pathogenesis of these events is unclear.     

Effects of oral magnesium supplementation on acute experimental cyclosporin nephrotoxicity

Hypomagnesaemia with magnesuria are common findings in cyclosporin-(CsA)-treatedpatients and have been proposed as both a cause and a consequenceof nephrotoxicity. To investigate the role of Mg depletion inthe pathogenesis of acute CsA nephrotoxicity, rats kept on alow-salt diet were maintained on plain water (Mg(–)group)or water supplemented with 2% MgCl₂ (Mg(+) group) and randomlyassigned to treatment with CsA 15mg/kg (CsA) or vehicle (VH)s.c. for 7 days. Water and food ingestion in VH animals wasadjusted to the intake of CsA animals. CsAMg(–)group showeda significant plasma magnesium (PMg) reduction as compared tobaseline (1.13 versus 1.53 mg/dl, P<0.001) or VH values (versus1.60 mg/dl, P< 0.001) and a significantly greater post-treatmentfractional excretion of magnesium (FeMg) as compared to VH (9.4versus 5.4%, P<0.0l). Magnesium supplementation increasedPMg (2.11 versus 1.57 mg/dl P<0.001) and FeMg (13.6 versus6.2%, P<0.001) but did not prevent a reduction in GFR withCsA treatment. Alanine aminopeptidase (AAP) excretion at 7 dayswas significantly greater than baseline (130 versus 44 IU/gCr,P<0.05) or VH (36 IU/gCr, P<0.05) values only in the CsAMg(–)rats. No differences were observed in intraerythrocyte Mg, bloodpressure, and urinary excretion of N-acetyl ß-D-glucosaminidaseamong groups. Renal histology was similar in CsA rats independentof magnesium supplementation: mild vacuolization and tubularcollapse in proximal tubules. In conclusion, Mg depletion couldnot be implicated in the pathogenesis of acute CsA-induced glomerulardysfunction, but Mg replacement may protect from some of thetubular toxicity of CsA.     

Direct transfer of hepatocyte growth factor gene into kidney suppresses cyclosporin A nephrotoxicity in rats.

BACKGROUND: The clinical utility of cyclosporin A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis and progressive renal impairment. Hepatocyte growth factor (HGF), which plays diverse roles in the regeneration of the kidney following acute renal failure, has been reported to protect against and salvage renal injury by acting as a renotropic and anti-fibrotic factor. Here, we investigated protective effects of HGF gene therapy on CsA-induced nephrotoxicity by using an electroporation-mediated gene transfer method. METHODS: CsA was orally administered as a daily dose of 30 mg/kg in male Sprague-Dawley rats receiving a low sodium diet (0.03% sodium). Plasmid vector encoding HGF (200 micro g) was transferred into the kidney by electroporation. RESULTS: HGF gene transfer resulted in significant increases in plasma HGF levels. Morphological assessment revealed that HGF gene transfer reduced CsA-induced initial tubular injury and inhibited interstitial infiltration of ED-1-positive macrophages. In addition, northern blot analysis demonstrated that cortical mRNA levels of TGF-beta and type I collagen were suppressed in the HGF group. Finally, HGF gene transfer significantly reduced striped interstitial phenotypic alterations and fibrosis in CsA-treated rats, as assessed by alpha-smooth muscle actin expression and Masson's trichrome staining. CONCLUSIONS: These results suggest that HGF may prevent CsA-induced tubulointerstitial fibrosis, indicating that HGF gene transfer may provide a potential strategy for preventing renal fibrosis.     

Protective effect of aminoguanidine against nephrotoxicity induced by amikacin in rats

Aminoglycoside antibiotics have long been used in antibacterial therapy. Despite their beneficial effects, aminoglycosides have considerable nephrotoxic and ototoxic side effects. It has been reported that reactive oxygen radical species (ROS) play role in the pathophysiology of aminoglycosides-induced nephrotoxicity. Aminoguanidine (AG) is an effective antioxidant and free radical scavenger which has long been known to protect against nephrotoxicity. We investigated the effects of AG on amikacin (AK)-induced changes of renal malondialdehyde (MDA), glutathione (GSH), blood urea nitrogen (BUN), serum creatinine (Cr) and albumin (Alb) which are used to monitor the development of renal tubular damage. Morphological changes in the kidney were also examined using light microscopy. A total of 21 rats were equally divided into three groups which were: (1) injected with saline, (2) injected with AK, and (3) injected with AK+AG, respectively. AK administration to control rats increased renal MDA and decreased GSH levels. AG administration before AK injection caused significant decreases in MDA and increases in GSH levels in kidneys compared to rats treated with AK alone. The serum BUN level increased slightly, Cr and serum Alb did not change as a result of any treatment. AG tended to decrease the level of serum BUN and did not cause any change in Alb or Cr levels. Morphological changes, including glomerular, tubular epithelial alterations and interstitial edema, were clearly observed in AK-treated rats. In addition, AG reversed the morphological damage to the kidney induced by AK. The results show that AG has a protective effect on nephrotoxicity induced by AK and may therefore improve the therapeutic index of AK.     

Effect of chronic theophylline administration on amphotericin B nephrotoxicity in rats

The effect of chronic theophylline administration on amphotericin B nephrotoxicity was investigated in rats. A 7-day treatment of amphotericin B (5 mg/kg/day i.p.) significantly reduced the glomerular filtration rate (GFR) measured as inuline clearance and creatinine clearance (0.74 +/- 0.29 and 0.16 +/- 0.04 ml/min, respectively) in comparison to vehicle-treated rats (2.04 +/- 0.23 and 1.29 +/- 0.19 ml/min, respectively). The reduced GFR led to evaluations in serum creatinine and BUN concentrations (0.94 +/- 0.09 and 78 +/- 11 mg/dl) in comparison to their own values before treatment (0.45 +/- 0.11 and 19 +/- 3 mg/dl). In addition amphotericin B induced an increase in sodium and a decrease in potassium excretion, the fractional sodium excretion was elevated 50-fold. The methylxanthine, theophylline, had a beneficial effect on the outcome of amphotericin-B-induced renal failure. The inuline clearance was 1.17 +/- 0.04 ml/min, the creatinine clearance 0.43 +/- 0.03 ml/min, the serum creatinine concentration 0.76 +/- 0.05 mg/dl and the BUN concentration 40 +/- 6 mg/dl. Theophylline had no effect on total sodium excretion and potassium excretion. The fractional sodium excretion, however, improved significantly. Theophylline as well as sodium deoxycholate, the detergent of amphotericin B, given alone had no effect on renal hemodynamics measured after 7 days.