Altered EGF expression and thyroxine metabolism in kidneys following acute ischemic injury in rat

To define the relationship between renal epidermal growth factor (EGF) expression and thyroid hormones in acute renal failure, we performed an analysis of the renal thyroid hormone-EGF axis following acute ischemic renal injury in rats. Levels of mature EGF extractable from kidney were elevated 24 h postinjury, and levels of membrane-associated EGF precursor were reduced. Administration of triiodothyronine (T-3) to rats, either prior to or immediately following the induction of injury, did not further increase levels of extractable EGF. Levels of EGF mRNA in kidneys were reduced 24 h following acute ischemic damage and not affected by administration of T-3. Enhanced production of mature EGF from EGF precursor occurred in membranes isolated from kidneys of rats 24 h postinjury compared with production in membranes from kidneys of normal rats. In addition, levels of thyroxine 5'-deiodinase activity in renal membranes were increased 24 h following injury. Levels of circulating total thyroxine (T-4), free T-4, and free T-3 were reduced postischemic injury. Total T-3 was unchanged. The administration of T-3 to normal rats increased renal 5'-deiodinase activity and EGF precursor cleavage. Administration of propylthiouracil to rats inhibited renal 5'-deiodinase activity and prevented the increase in extractable EGF postischemic injury. We conclude that the increase in levels of mature EGF extractable from kidneys of rats postischemic injury results from enhanced activity of the serine protease that cleaves the EGF precursor. This activity may be stimulated by T-3 produced in kidney. These alterations in renal T-4 metabolism and EGF expression could serve to facilitate recovery of renal function following ischemia.