Endothelin and cyclosporine nephrotoxicity

Although some humoral and neural factors have been implicated in the persistent vasoconstriction characterizing many forms of acute renal failure, the mechanisms for this abnonnal vascular function have remained largely unresolved. Several factors previously postulated to have a role in acute renal failure have been shown to enhance endothelin (Et) production or gene expression. We studied the potential pathophysiologic role for Et in several models of acute renal failure, including postischemia, endotoxin, and cyclosponne (Cy) nephrotoxicity. We have found that, in vivo, Cy (and also endotoxin) elevates circulating Et. We further showed that antagonizing Et s action with Et antibody ameliorates renal vasoconstriction following renal ischemia, Cy, and endotoxin administrntion. Additionally, our studies showed that even afer circulating levels of Et decrease following Cy), there is upregulation in Et receptors in the kidneys. Overall, endothelin appears to feature prominently in the pathophysiologic processes occum'ng during seveml forms of acute renal failure.