TY - JOUR
T1 - Cyclosporine nephrotoxicity
T2 - Attenuation by an antioxidant-inhibitor of lipid peroxidation in vitro and in vivo
AU - Wang, Chunyou
AU - Salahudeen, Abdulla K.
PY - 1994/10/27
Y1 - 1994/10/27
N2 - The exact mechanism by which cyclosporine (CsA) causes renal injury is not known. The possibility that reactive oxygen species (ROS) may play a role, since CsA induces renal microsomal lipid peroxidation and reduces glutathione levels, was investigated by examining whether administration of an antioxidant attenuates CsA-induced nephrotoxicity. One of three groups of uninephrectomized rats received vehicles, another CsA 25 mg/kg/day and the third, CsA plus antioxidant lazaroid (U-74389 G) 20 mg/kg/day, for 8 weeks. CsA-induced functional and structural derangements were accompanied by a significant induction of renal cortical lipid peroxidation (thiobarbitu-ric acid reactive substances and conjugated diene). Administration of lazaroid significantly suppressed CsA-induced lipid peroxidation and provided significant functional and structural protection. That lazaroid affords renal functional protection against CsA in the rat was again demonstrable in a crossover study. To examine the relation between CsA nephrotoxicity and lipid peroxidation, cell culture studies were undertaken. CsA induced renal epithelial (LLC-PKj) cell injury (LDH release) as well as lipid peroxidation and degradation (prelabeled 8H arachidonic acid release). Lazaroid prevented CsA-induced cell injury and limited lipid alterations. These new findings—that an antioxidant inhibitor of lipid peroxidation limits CsA-induced renal toxicity in vitro and in vivo—suggest a pathogenic role for ROS-mediated lipid peroxidation in CsA-induced renal toxicity. Antioxidant therapy may minimize CsA-induced renal toxicity in humans.
AB - The exact mechanism by which cyclosporine (CsA) causes renal injury is not known. The possibility that reactive oxygen species (ROS) may play a role, since CsA induces renal microsomal lipid peroxidation and reduces glutathione levels, was investigated by examining whether administration of an antioxidant attenuates CsA-induced nephrotoxicity. One of three groups of uninephrectomized rats received vehicles, another CsA 25 mg/kg/day and the third, CsA plus antioxidant lazaroid (U-74389 G) 20 mg/kg/day, for 8 weeks. CsA-induced functional and structural derangements were accompanied by a significant induction of renal cortical lipid peroxidation (thiobarbitu-ric acid reactive substances and conjugated diene). Administration of lazaroid significantly suppressed CsA-induced lipid peroxidation and provided significant functional and structural protection. That lazaroid affords renal functional protection against CsA in the rat was again demonstrable in a crossover study. To examine the relation between CsA nephrotoxicity and lipid peroxidation, cell culture studies were undertaken. CsA induced renal epithelial (LLC-PKj) cell injury (LDH release) as well as lipid peroxidation and degradation (prelabeled 8H arachidonic acid release). Lazaroid prevented CsA-induced cell injury and limited lipid alterations. These new findings—that an antioxidant inhibitor of lipid peroxidation limits CsA-induced renal toxicity in vitro and in vivo—suggest a pathogenic role for ROS-mediated lipid peroxidation in CsA-induced renal toxicity. Antioxidant therapy may minimize CsA-induced renal toxicity in humans.
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U2 - 10.1097/00007890-199410270-00014
DO - 10.1097/00007890-199410270-00014
M3 - Article
C2 - 7940739
AN - SCOPUS:0028114647
SN - 0041-1337
VL - 58
SP - 940
EP - 946
JO - Transplantation
JF - Transplantation
IS - 8
ER -