Clinical toxicities of immunosuppressants
Nephrotoxicity
Magnesium Supplementation Prevents Chronic Cyclosporine Nephrotoxicity via Adjusting Nitric Oxide Synthase Activity

https://doi.org/10.1016/j.transproceed.2005.02.098Get rights and content

Abstract

Introduction

Nitric oxide synthase (NOS) is a protective factor for chronic cyclosporine nephrotoxicity by virtue of adjusting the production of nitric oxide (NO). The aim of this study was to explore the role of NOS in the effect of magnesium supplementation to prevent chronic cyclosporine nephrotoxicity.

Methods

Rats maintained on a low-salt diet were divided into three groups: normal controls, cyclosporine group (CsA 15 mg · kg−1 · d−1 subcutaneously) and CsA + Mg2+ group (CsA subcutaneously and dietary supplementation with 0.6% Mg enriched by MgCl2). On day 28, plasma Mg2+, plasma creatinine, NOS activity, and NO content in renal tissue were examined. The renal expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in kidneys was determined by an immunohistochemistry technique. The lesions of chronic cyclosporine nephrotoxicity were identified by HE and PAS stains as well as electron microscope.

Results

After 28 days of CsA administration, characteristic histological lesions of chronic cyclosporine nephotoxicity were observed, including arteriolopathy, tubular atrophy and interstitial fibrosis. Giant mitochondria and microcalcifications were observed by electron microscopy. Simultaneously, constitutive nitric oxide synthase (cNOS) activity in kidneys was increased, but NO content did not increase correspondingly (P < .05) compared with normal controls. Dietary supplementation with Mg2+ ameliorated the CsA-induced histological lesions. cNOS activity was decreased to normal levels and NOS was increased (P < .05) compared with animals that only received CsA. CsA and magnesium supplementation did not change iNOS activity.

Conclusions

Dietary supplementation with Mg2+ seems to improve renal function and almost abolish CsA-induced histological lesions via altering the abnormal activation of cNOS in this model.

Section snippets

Animal

The present experiments were conducted in accord with the National Institutes of Health Guide for Care and Use of Laboratory Animals. A total of 21 male Wistar rats with body weights between 180 and 220 g were obtained from the Laboratory Animal Center of Hubei Province, China. All rats were allowed free access to standard rat chow for a week. Rats were then housed in a temperature- and light-controlled environment while receiving a semisynthetic low sodium (0.05% sodium) and normal Mg (0.05%

Physiological Study

Physiological parameters are summarized in Table 1. The final body weights of rats in the Mg supplementation group were significantly less than those in the CsA group or the normal control group (CsA + Mg vs CsA, P < .05). On day 28, plasma Mg concentration declined markedly with the duration of CsA treatment (CsA group vs control group, P < .05). Dietary supplementation with Mg attenuated the CsA-induced hypomagnesemia (CsA group vs CsA + Mg group, P < .05).

Plasma creatinine concentration

Discussion

In this study, the histological lesions of chronic cyclosporine nephrotoxicity were observed in rats administered the drug: arteriolopathy, tubular atrophy, tubulointerstitial fibrosis, and thickening of glomerular basement membrane. Oral Mg supplementation markedly attenuated the development of lesions induced by CsA; the Pcr was lower than in the CsA group, strongly suggesting that the renal function deterioration elicited by drug treatment was improved.

NO generated by nNOS within the macula

References (11)

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Supported by the Chinese National Basic Research Program (973 Program, No. 2003CB515505).

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