Toshihiro Asai

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

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.

Role of hypomagnesemia in chronic cyclosporine nephropathy

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.

Activation of transcription factors AP-1 and NF-κB in chronic cyclosporine a nephrotoxicity: Role in beneficial effects of magnesium supplementation

Background. It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-&kgr;B 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-&kgr;B in renal cortex were determined by electrophoretic mobility shift assay. Results. DNA-binding activity of AP-1 and NF-&kgr;B 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-&kgr;B was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28. Conclusions. Renal cortical AP-1 and NF-&kgr;B 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.