Publications by authors named "Toshihiro Asai"

16 Publications

  • Page 1 of 1

Pharmacokinetic study of interleukin-2 following intravenous injection in hemodialysis patients with renal cell carcinoma.

Ther Apher Dial 2008 Feb;12(1):67-71

Department of Urology, Osaka City General Hospital, Miyakojimaku, Osaka, Japan.

The purpose of the present study is to determine the change in blood concentration of interleukin-2 (IL-2) after intravenous injection in hemodialysis patients and to assess its safety. Four hemodialysis patients who underwent nephrectomy due to renal cell carcinoma were treated with IL-2 at a dose of 350 000-700 000 JRU by intravenous injection. Pharmacokinetic parameters were analyzed from the serum IL-2 concentration, which reached its peak just after the end of infusion, followed by biphasic elimination, and was below the detection limit in all patients at 24 h postinfusion. In comparison with patients with normal renal function, the volume of distribution in the serum compartment was almost comparable (3820 +/- 2020 mL). Clearance (50.47 +/- 11.50 mL/min) decreased to 40%, and the half-life of the distribution phase (0.45 +/- 0.19 h) and that of the terminal phase (1.72 +/- 0.20 h) were distinctly longer. The area under the blood concentration-time curve was about two-fold higher than that of non-hemodialysis patients. In all patients, there were no serious adverse reactions. The results of the present study suggest that intravenous IL-2 therapy can be safely performed in hemodialysis patients.
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http://dx.doi.org/10.1111/j.1744-9987.2007.00543.xDOI Listing
February 2008

The Fas/Fas-ligand pathway does not mediate the apoptosis in elastase-induced emphysema in mice.

Exp Lung Res 2007 Aug;33(6):277-88

Second Department of Internal Medicine, Regeneration and Advanced Medical Science, Graduate School of Medicine, Gifu University, Gifu, Japan.

Porcine pancreatic elastase (PPE), which induces emphysema via apoptosis, was administered to wild-type and Fas-deficient (lpr) mice. On days 3 and 28 after administration, the mean linear intercepts within lung tissues were significantly higher in PPE-treated wild-type and lpr mice than in control mice, though there were no significant differences between the PPE-treated groups. Likewise, the numbers of TUNEL-positive cells were increased in the lungs of PPE-treated wild-type and lpr mice, and again the effect was similar in the two PPE-treated groups. These findings suggest that apoptosis associated with PPE-induced emphysema is not mediated via the Fas/Fas-ligand pathway.
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http://dx.doi.org/10.1080/01902140701509458DOI Listing
August 2007

Narirutin inhibits airway inflammation in an allergic mouse model.

Clin Exp Pharmacol Physiol 2007 Aug;34(8):766-70

Second Department of Internal Medicine, Regeneration and Advanced Medical Science, Graduate School of Medicine, Gifu University, Gifu, Japan.

1. Flavonoids are naturally occurring compounds that possess anti-allergic, anti-inflammatory, antiproliferative and anti-oxidant properties. In the present study, we investigated whether the flavonoid narirutin could reduce airway inflammation in ovalbumin (OVA)-sensitized/challenged NC/Nga mice, a model of allergic eosinophilic airway inflammation. 2. Mice were initially immunized intraperitoneally with OVA on Days 0 and 7 and then challenged with inhaled OVA on Days 14, 15 and 16. In addition, some mice received narirutin orally at doses of 0.1, 1 or 10 mg/kg bodyweight daily on Days 7-16. 3. At 10 mg/kg, but not 0.1 or 1 mg/kg, narirutin significantly diminished OVA-induced airway inflammation caused by infiltration of lung tissue with inflammatory and mucus-producing cells, as well as reduced eosinophil counts in the peripheral blood and bronchoalveolar lavage fluid (BALF), interleukin (IL)-4 levels in BALF and IgE levels in serum. 4. The mechanism of the anti-inflammatory effect of narirutin are likely to be associated with a reduction in the OVA-induced increases of IL-4 and IgE in a murine model of allergic eosinophilic airway inflammation. These findings suggest that narirutin may be an effective new tool in the treatment of bronchial asthma.
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http://dx.doi.org/10.1111/j.1440-1681.2007.04636.xDOI Listing
August 2007

The specific free radical scavenger edaravone suppresses bleomycin-induced acute pulmonary injury in rabbits.

Clin Exp Pharmacol Physiol 2007 Jan-Feb;34(1-2):22-6

Second Department of Internal Medicine, Regeneration and Advanced Medical Science, Graduate School of Medicine, Gifu University, Gifu, Japan.

1. Intratracheal instillation of bleomycin induces a condition in rabbits that serves as a useful model of human pulmonary fibrosis. Bleomycin-induced production of reactive oxygen species leads to acute lung inflammation and induction of apoptosis, which is followed by pulmonary fibrosis at a later chronic stage. In the present study, we tested whether edaravone, a free radical scavenger, would suppress bleomycin-induced acute pulmonary inflammation. 2. Rabbits were divided into three groups (n = 10 in each): (i) a bleomycin-treated group, which received intratracheal instillation of 2 mg/kg bleomycin; (ii) a bleomycin + edaravone group, which received a 10 day regimen of daily intravenous injections of edaravone (3 mg/kg per day) beginning 3 days before bleomycin instillation; and (iii) a saline control group. Rabbits were killed for analysis 7 days after bleomycin administration. 3. In lung tissues from the bleomycin-treated group, marked infiltration of inflammatory cells, consisting mainly of lymphocytes, neutrophils and eosinophils, was observed. In addition, significantly increased numbers of TUNEL-positive (apoptotic) and transforming growth factor-beta-positive cells were seen. All these effects were significantly attenuated by treatment with edaravone. 4. The findings of the present study suggest that edaravone may be useful in the prevention of acute lung injury resulting from the production of reactive oxygen species.
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http://dx.doi.org/10.1111/j.1440-1681.2007.04528.xDOI Listing
March 2007

Beneficial effects of autologous bone marrow mononuclear cell transplantation against elastase-induced emphysema in rabbits.

Exp Lung Res 2006 Oct;32(9):413-26

Second Department of Internal Medicine, Regeneration and Advanced Medical Science, Graduate School of Medicine, Gifu University, Gifu, Japan.

The authors investigated whether autologous bone marrow mononuclear cell (BMC) transplantation via the left and right main bronchi would mitigate elastase-induced pulmonary emphysema in rabbits. Four weeks after elastase administration, rabbits also receiving BMCs showed significantly better pulmonary function (FVC, FEV100, FEVPEF) and smaller alveolar airspaces, as indicated by a smaller mean linear intercept, than those receiving porcine pancreatic elastase (PPE) (200 U/kg) alone via the left and right main bronchi. BMCs also significantly reduced cell counts in bronchoalveolar lavage fluid, the incidence of apoptotic (TUNEL-positive) cells and matrix metalloproteinase (MMP)-2 expression, while increasing numbers of proliferative (Ki-67-positive) cells. Thus, BMCs may inhibit the progression to emphysema by attenuating inflammation, MMP-2 expression, and apoptosis, while enhancing alveolar cell proliferation.
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http://dx.doi.org/10.1080/01902140601047633DOI Listing
October 2006

Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis.

J Pharmacol Sci 2006 Jan 6;100(1):17-21. Epub 2006 Jan 6.

Department of Urology, Osaka City University Medical School, Osaka, Japan.

Tubulointerstitial fibrosis is a common feature of many progressive renal diseases and is a main determinant that leads to an irreversible loss of renal function. In chronic cyclosporin A nephrotoxicity, we previously reported that inflammatory responses such as macrophage infiltration preceded interstitial fibrosis. This inflammation was accompanied by an elevation in renal nuclear factor kappaB (NF-kappaB) activity. Similar findings were obtained in chronic tacrolimus nephrotoxicity and obstructive nephropathy. Inhibition of NF-kappaB markedly attenuated renal inflammation and interstitial fibrosis in these models. Furthermore, administration of oral adsorbent (Kremezin) significantly attenuated the increase in renal NF-kappaB activity and concomitantly reduced interstitial inflammation and renal fibrosis in chronic renal failure rats. Elimination of indoxyl sulfate by this adsorbent is likely involved in this mechanism since it is known that indoxyl sulfate activates NF-kappaB in renal tubular cells. It is suggested that strategy aiming at NF-kappaB inhibition is important to prevent the progression of renal fibrosis.
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http://dx.doi.org/10.1254/jphs.fmj05003x4DOI Listing
January 2006

[A case of chronic obstructive pulmonary disease (COPD) successfully treated by acupuncture].

Nihon Kokyuki Gakkai Zasshi 2005 May;43(5):289-95

Department of Oriental Medicine, Gifu University of Medicine.

Chronic obstructive pulmonary disease (COPD) involves a decrease in respiratory function and limits daily activities. We report a COPD patient whose respiratory symptoms were improved by acupuncture treatment. A 66-year-old man visited Gifu University Hospital with breathlessness on exercise. Despite medication, his general condition worsened. A series of acupuncture treatments was subsequently started on October 27, 2001. He had level III breathlessness on JRS classification prior to acupuncture treatment, and his respiratory function parameters were VC: 3.54 L, FEV1: 1.19 L, FEV1% (G): 33.6% and %FEV1: 45%. The basic meridian points used were KI 3 (Fuliu), LU 9 (Taiyuan), LU 1 (Zhongfu), CV 12 (Zhongwan), CV 4 (Guanyuan), BL 13 (Feishu), and BL 23 (Shenshu). The acupuncture needles were retained for ten minutes in each session. This research design was used to detect the specific efficacy of acupuncture treatment After ten acupuncture treatments over two months, his walking distance, Borg scale and respiratory function were improved compared with before treatment. These findings suggest that acupuncture treatment may be efficacious for advanced cases of COPD.
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May 2005

A < 1.7 cM interval is responsible for Dmo1 obesity phenotypes in OLETF rats.

Clin Exp Pharmacol Physiol 2004 Jan-Feb;31(1-2):110-2

Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.

1. Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes of male Otsuka Long Evans Tokushima Fatty (OLETF) rats. 2. Our congenic lines, produced by transferring Dmo1 chromosomal segments from the non-diabetic Brown Norway (BN) rat into the OLETF strain, have confirmed the strong, wide-range therapeutic effects of Dmo1 on dyslipidaemia, obesity and diabetes in the fourth (BC4) and fifth (BC5) generations of congenic animals. Analysis of a relatively small number of BC5 rats (n = 71) suggested that the critical Dmo1 interval lies within a < 4.9 cM region between D1Rat461 and D1Rat459. 3. To confirm the assignment of the Dmo1 critical interval, we intercrossed BC5 animals to produce a larger study population (BC5:F1 males; n = 406). For the present study, we used bodyweight at 18 weeks of age as an index of obesity; this phenotype is representative of the closely associated dyslipidaemia and hyperglycaemia phenotypes. 4. Interval mapping assigned logarithm of odds (LOD) peaks at the D1Rat90 marker (LOD = 9.11). One LOD support interval lies within the < 1.7 cM region between D1Rat461 and D1Rat459. 5. This large intercross study confirms that Dmo1 is likely localized within the interval.
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http://dx.doi.org/10.1111/j.1440-1681.2004.03959.xDOI Listing
September 2004

Possible involvement of nuclear factor-kappaB inhibition in the renal protective effect of oral adsorbent AST-120 in a rat model of chronic renal failure.

Int J Mol Med 2004 Jan;13(1):133-8

Department of Nephrology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku Osaka 545-8585, Japan.

Oral adsorbent, AST-120 removes uremic toxins (such as indoxyl sulfate) and retards the progression of chronic renal failure (CRF). However, its mechanism of action has not been precisely clarified. Since indoxyl sulfate elicits renal tubular nuclear factor-kappaB (NF-kappaB) activation in vitro, the present experiments were conducted to elucidate the involvement of NF-kappaB in the beneficial effects of AST-120 using rats with 3/4 nephrectomy, a model of early-stage CRF. Daily administration of AST-120 was started at 6 weeks after 3/4 nephrectomy and continued for 18 weeks. Sham-operated rats, untreated CRF rats and AST-120-treated CRF rats were compared for NF-kappaB DNA-binding activity, gene expression and renal histology. Systolic blood pressure was increased in CRF rats, and this increase was not affected by AST-120. Blood urea nitrogen, serum creatinine and urinary protein were increased in CRF rats. Although AST-120 attenuated these increases, it did not do so to a statistically significant extent. Indoxyl sulfate, which was accumulated in serum of CRF rats, was significantly eliminated by AST-120. Renal cortical NF-kappaB DNA-binding activity was increased in CRF rats. AST-120 significantly inhibited this increase. Monocyte/macrophage infiltration and increased monocyte chemoattractant protein-1 (MCP-1) mRNA observed in CRF rats were attenuated by AST-120. Furthermore, AST-120 significantly blocked renal fibrosis with concomitant inhibition of transforming growth factor beta1 (TGF-beta1) gene expression. It appeared that AST-120 reduced NF-kappaB activation and possibly the activity of NF-kappaB-dependent pathways of interstitial inflammation including MCP-1 expression and macrophage infiltration. The anti-inflammatory effect of AST-120 mediated via inhibition of NF-kappaB is a possible mechanism by which AST-120 retards the progression of renal fibrosis in CRF.
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January 2004

Attenuation of renal fibrosis by proteasome inhibition in rat obstructive nephropathy: possible role of nuclear factor kappaB.

Int J Mol Med 2003 Oct;12(4):587-92

Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka 545-8585, Japan.

We previously reported that pyrrolidine dithiocarbamate blocked nuclear factor-kappaB (NF-kappaB) activation and attenuated interstitial inflammation and tubulointerstitial fibrosis in the rat obstructive nephropathy. Since pyrrolidine dithiocarbamate is an anti-oxidant and possesses additional biological properties, present experiment was conducted to clarify further the role of NF-kappaB in the development of tubulointerstitial fibrosis in obstructed kidney using a proteasome inhibitor that blocks NF-kappaB through stabilizing IkappaB, an endogenous inhibitor of NF-kappaB. At 5 days following unilateral ureteral obstruction (UUO) in rats, obstructed kidney exhibited tubulointerstitial fibrosis that was associated with macrophage infiltration. UUO decreased renal cortical IkappaB protein contents with concomitant increases in NF-kappaB DNA-binding activity and gene expression of monocyte chemoattractant protein-1. Administration of PSI, N-benzyloxy-carbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal, a proteasome inhibitor, (3 mg/kg/day, s.c., b.i.d) to UUO rats inhibited proteasome activity and attenuated the changes in IkappaB content, NF-kappaB activity and MCP-1 mRNA expression observed in UUO rats. PSI also decreased macrophage influx and attenuated the development of fibrosis. Furthermore, up-regulated gene expression of pro-fibrogenic molecules observed in the obstructed kidney was attenuated by PSI. These results further support the notion that NF-kappaB plays an important role in the development of renal fibrosis in the obstructive nephropathy.
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October 2003

Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation.

Transplantation 2003 Apr;75(7):1040-4

Department of Urology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.

Background: It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB play a pivotal role in various renal diseases. We aimed to study their activations in chronic cyclosporine A (CsA) nephrotoxicity and evaluate the effect of magnesium (Mg) supplementation and blockade of the renin-angiotensin system (RAS), which are known to ameliorate CsA nephrotoxicity, on these transcription factors.

Methods: CsA (15 mg/kg/day) was administered subcutaneously daily to rats maintained on a low-sodium diet for 7, 14, and 28 days. DNA-binding activities of AP-1 and NF-kappaB in renal cortex were determined by electrophoretic mobility shift assay.

Results: DNA-binding activity of AP-1 and NF-kappaB started to increase at day 14 and further elevated at day 28 by CsA treatment. These activations were markedly attenuated when rats were maintained on a high-Mg diet. In contrast, angiotensin-converting enzyme inhibitor (ACEI) had no effect on CsA-induced AP-1 activation. CsA-induced activation of NF-kappaB was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28.

Conclusions: Renal cortical AP-1 and NF-kappaB DNA binding were activated in chronic CsA nephrotoxicity. These activations were induced largely by means of RAS-independent mechanisms. It is suggested that prevention of CsA-induced DNA-binding activation of these transcription factors is at least in part responsible for the beneficial effects of Mg supplementation on CsA nephrotoxicity.
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http://dx.doi.org/10.1097/01.TP.0000057242.96219.AFDOI Listing
April 2003

[Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity].

Hinyokika Kiyo 2002 Nov;48(11):699-705

Department of Urology, Osaka City University Graduate School of Medicine.

Immunosuppressant-induced nephrotoxicity contributes to kidney graft loss in the long-term as one of the non-immunologic factors. We previously reported that correction of cyclosporine A (CsA)-induced hypomagnesemia reduced chronic CsA nephrotoxicity. This study was conducted to elucidate the mechanism of the beneficial effects of magnesium (Mg) on CsA nephrotoxicity and examine the role of the renin-angiotensin system in this mechanism. We particularly focused on CsA-induced interstitial mononuclear cell infiltration. CsA (15 mg/kg/day, s.c.) was administered daily to rats maintained on low sodium diets for 7, 14 and 28 days. The inhibitory effects of Mg supplementation and those of angiotensin converting enzyme inhibitor (ACEI) were compared for renal function, renal histology, mononuclear cell infiltration and gene expression profile. CsA lowered creatinine clearance and developed characteristic tubulointerstitial fibrosis that were mostly evident at day 28. CsA-induced impairment of renal function was ameliorated by Mg supplementation but not by ACEI. Monocyte/macrophage infiltration preceded the renal fibrosis and increased progressively with the duration of CsA administration. CsA markedly upregulated the expression of chemoattractant proteins, osteopontin and monocyte chemoattractant protein-1, concomitantly. These changes were markedly attenuated by Mg but only slightly by ACEI. CsA also promoted expression of fibrogenic molecules and extracellular matrices that were markedly attenuated by Mg but only slightly by ACEI. Similarly, CsA-induced tubulointestitial fibrosis was almost completely abolished by Mg supplementation but only partially attenuated by ACEI. These results suggested that Mg supplementation abolished CsA-induced precedent inflammatory cell influx possibly via inhibition of expression of chemoattractants and consequently suppressed tubulointerstitial fibrosis. In this beneficial mechanism, factors independent of renin-angiotensin system seem to be mainly involved.
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November 2002

Role of renin-angiotensin system and nuclear factor-kappaB in the obstructed kidney of rats with unilateral ureteral obstruction.

Jpn J Pharmacol 2002 Dec;90(4):361-4

Department of Urology, Osaka City University, Japan.

The present study was conducted to elucidate the role of oxidative stress and nuclear factor-kappaB (NF-kappaB) in the beneficial effects of angiotensin receptor blockade on obstructive nephropathy. Unilateral ureteral occlusion in rats elicited tubulo-interstitial fibrosis with concomitant macrophage infiltration and increased expression of monocyte chemoattractant protein-1. These changes were accompanied by an induction of renal cortical lipid peroxidation and activation of NF-kappaB. Both an AT(1) antagonist, candesartan, and a NF-kappaB inhibitor, pyrrolidine dithiocarbamate, markedly attenuated these changes and to a similar extent. These results suggest that the beneficial effects of angiotensin blockade are mediated by the inhibition of oxidative stress and subsequent NF-kappaB activation in obstructive nephropathy.
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http://dx.doi.org/10.1254/jjp.90.361DOI Listing
December 2002

Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate prevents chronic FK506 nephropathy.

Kidney Int 2003 Jan;63(1):306-14

Department of Urology, Osaka City University, Osaka, Japan.

Background: Chronic tacrolimus (FK506) nephrotoxicity is characterized by renal fibrosis with interstitial inflammation. Since nuclear factor-kappaB (NF-kappaB) plays a key role in chronic inflammatory diseases including renal disease, the present study was conducted to elucidate the role of NF-kappaB in the pathogenesis of chronic FK506-induced nephropathy.

Methods: FK506 (1 mg/kg/day, SC) was administered daily to rats maintained on low sodium diet for 42 days. Some rats were treated with a putative NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100, 200 mg/kg/day, by gavage). The renal function, renal histology, renal NF-kappaB-DNA binding activity and gene expression profile were examined.

Results: FK506 caused a decline in glomerular filtration and induced characteristic renal morphologic changes including arteriolopathy, tubular atrophy and interstitial fibrosis. FK506 markedly activated renal cortical NF-kappaB-DNA binding. PDTC administration inhibited NF-kappaB-DNA binding activity in a dose dependent manner. With higher dose, NF-kappaB-DNA binding activity was decreased to a control level. PDTC had little effect on FK506-induced renal dysfunction. Renal cortical monocyte/macrophage infiltration observed in FK506-treated rats was dramatically suppressed by PDTC. FK506 up-regulated renal cortical gene expression of chemoattractant proteins, monocyte chemoattractant protein-1 (MCP-1) and osteopontin. PDTC significantly blocked MCP-1 gene expression but had no effect on osteopontin gene expression. Tubular atrophy and tubulointerstitial fibrosis, but not arteriolopathy, were significantly attenuated by PDTC. FK506 increased renal mRNA expression of fibrogenic molecules and extracellular matrices that also were attenuated by PDTC treatment.

Conclusions: NF-kappaB plays an important role in mediating cortical monocyte/macrophage infiltration and in the pathogenesis of tubular injury and interstitial fibrosis in experimental FK506-induced chronic nephropathy.
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http://dx.doi.org/10.1046/j.1523-1755.2003.00714.xDOI Listing
January 2003

Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism.

Transplantation 2002 Sep;74(6):784-91

Department of Pharmacology, Osaka City University Medical School, Abeno, Japan.

Background: We have previously shown that correction of hypomagnesemia by magnesium (Mg) supplementation ameliorates chronic cyclosporine A (CsA) nephropathy via inhibiting gene expression of fibrogenic molecules. Experiments were conducted to further elucidate upstream mechanism of the beneficial effects upon CsA nephrotoxicity.

Methods: CsA (15 mg/kg/day, subcutaneous [SC]) was administered daily to rats maintained on low sodium diet for 7, 14, and 28 days. Because blockade of renin-angiotensin system improves chronic CsA nephropathy, the effects of Mg supplementation and those of angiotensin-converting enzyme inhibitor (ACEI) were compared on renal function, renal histology, mononuclear cell infiltration, and gene expression profile.

Results: CsA induced a decline in glomerular filtration and developed characteristic striped fibrosis that were mostly evident at day 28. Mg attenuated CsA-induced impaired renal function, whereas ACEI did not. Interstitial inflammation as evidenced by monocyte/macrophage infiltration preceded the renal fibrosis and increased progressively with the CsA treatment period. Concomitantly, CsA markedly up-regulated expression of chemoattractant proteins, osteopontin, and monocyte chemoattractant protein-1. These changes were abolished by Mg but were only partially affected with ACEI. CsA promoted renal mRNA expression of fibrogenic molecules and extracellular matrices that were almost completely abolished by Mg but partially suppressed by ACEI. Similarly, CsA-induced chronic fibrotic lesion was markedly attenuated by Mg supplementation but was partially attenuated by ACEI.

Conclusion: Mg supplementation abolished CsA-induced precedent interstitial inflammation possibly via inhibition of chemoattractants expression and consequently attenuated tubulointerstitial fibrosis. In this protective mechanism, factors independent of the renin-angiotensin system appears to be mainly involved.
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http://dx.doi.org/10.1097/00007890-200209270-00009DOI Listing
September 2002

Role of hypomagnesemia in chronic cyclosporine nephropathy.

Transplantation 2002 Feb;73(3):340-7

Department of Pharmacology, Osaka City University Medical School, Abeno, Osaka, Japan.

Background: Hypomagnesemia is a common finding of cyclosporine (CsA)-treated patients and has been proposed as both a cause and a consequence of CsA-induced nephrotoxicity. This experiment was conducted to elucidate the role of hypomagnesemia in the pathogenesis of chronic CsA nephropathy.

Methods: CsA (15 mg/kg/day subcutaneously) was administered to rats maintained on a low-sodium diet for 1, 2, and 4 weeks, and the effects of magnesium (Mg) supplementation on renal function, renal histology, and renal gene expression profile of fibrogenic molecules and vasoconstrictors was examined.

Results: CsA elicited hypomagnesemia and induced a progressive decline in glomerular filtration. At 28 day, renal tubular atrophy and cortical striped interstitial fibrosis were evident with CsA treatment. Dietary supplementation of Mg ameliorated CsA-induced hypomagnesemia and almost completely abolished CsA-induced chronic fibrotic lesions. Neither CsA nor Mg supplementation affected blood pressure. Renal cortical mRNA of transforming growth factor beta, plasminogen activator inhibitor (PAI)-1, and extracellular matrix started to increase at 14 days and elevated further at 28 days. In contrast, the increase in mRNA of tissue inhibitor of matrix metalloproteinase-1 and renin was evident early at 7 days and reached peak at 14 days. These mRNA increases, except that of renin, were almost abolished when hypomagnesemia was corrected. Magnesium supplementation also improved glomerular dysfunction, at least in part, through inhibition of up-regulated mRNA of endothelin-1.

Conclusion: CsA-induced hypomagnesemia contributes to chronic renal fibrotic lesions seen during CsA treatment through up-regulation of fibrogenic molecules, most notably early activation of tissue inhibitor of matrix metalloproteinase-1 expression.
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http://dx.doi.org/10.1097/00007890-200202150-00005DOI Listing
February 2002
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