Cellular and molecular mechanisms of cyclosporin nephrotoxicity.
Cyclosporin therapy is associated with several forms of nephrotoxicity, the most significant of which are reversible impairment of glomerular filtration and irreversible interstitial fibrosis. Impaired glomerular filtration is due to both reduction in Kf, the glomerular capillary ultrafiltration coefficient, and to reduction in renal blood flow. The mechanisms responsible for the low Kf are not well defined, but heightened mesangial cell contractility may contribute. Reduced renal blood flow with chronic cyclosporin therapy arises from both endothelial damage and altered eicosanoid metabolism, in particular increased thromboxane synthesis. Renal interstitial fibrosis, which develops in some patients after approximately 6-12 months of cyclosporin therapy, poses a major limitation to the chronic use of the drug. Two mechanisms likely contribute to cyclosporin-associated interstitial fibrosis. First, endothelial injury and vasoconstriction produce renal ischemia, which in turn is associated with enhanced synthesis of extracellular matrix proteins. Second, cyclosporin likely influences the accumulation of matrix proteins in the renal interstitium through nonhemodynamic mechanisms, as suggested by altered matrix accumulation in non-renal tissues. This effect of cyclosporin may be direct or indirect, via mediators including cytokines, peptide growth factors, and thromboxane. The molecular mechanisms of cyclosporin action on immunologic and mesenchymal cells are active areas of investigation. Intracellular targets of cyclosporin include mitochondrial respiration, cellular calcium signaling, protein kinase C, protein synthesis, and peptidyl-prolyl isomerases. However, the significance of these intracellular effects for cyclosporin nephrotoxicity remains to be demonstrated.
Kopp
J B
JB
Molecular Medicine Section, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
Klotman
P E
PE
D000591:Amino Acid Isomerases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003524:Cyclosporins / Q000009:adverse effects* / Q000378:metabolism / Q000633:toxicity; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D019696:Peptidylprolyl Isomerase; D011506:Proteins / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D002352:Carrier Proteins; D003524:Cyclosporins; D015777:Eicosanoids; D011506:Proteins; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase