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

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.