Angiotensin-Converting Enzyme Inhibition Induces Death Receptor Apoptotic Pathways in Erythroid Precursors following Renal Transplantation

Abstract

Background: Posttransplant erythrocytosis (PTE) is a condition that occurs in kidney transplant patients and is characterized by increase in hematocrit above 51%. While its pathogenesis remains unclear, angiotensin-converting enzyme inhibitors (ACEI) have been used successfully in the treatment of PTE. We have previously shown that ACEI induce apoptosis in the peripheral erythroid precursors from patients with PTE. In the current study we elucidate the molecular mechanisms of ACEI-induced apoptosis. Methods: Peripheral CD34+ cells were obtained from four normal controls, five normal kidney transplants, and six kidney transplants with PTE, before and after treatment with ACEI. We evaluated the expression of a variety of apoptotic factors by quantitative reverse transcription-multiplex polymerase chain reaction, Western blot and immunocytochemistry. Results: ACEI resulted in a significant induction of Fas, FADD, and TRADD mRNAs in renal transplant patients with or without PTE. No changes were noted in the expression of mRNAs encoding Bcl-2, Bcl-xL, Bax, caspase 8, caspase 3, or GAPDH. ACEI also resulted in a significant upregulation of Fas, FADD and TRADD protein expression, and their localization predominantly at the plasma membrane. Conclusions: Our results suggest that ACEI therapy induces apoptosis in erythrocyte progenitor cells of renal transplant patients at least in part via induction of death receptor apoptotic cascades.