Transcriptome analysis reveals heterogeneity in the injury response of kidney transplants

Abstract

We studied the transcripts that are increased by stress and injury in mouse kidney transplants, focusing on transcripts increased in parenchymal cells-injury and repair-induced transcripts (IRITs). We compared four types of stressed kidneys: isografts, allografts, host kidneys of mice with isografts and nontransplant kidneys with ischemic acute tubular necrosis (ATN). After excluding transcripts associated with infiltrating cells and interferon-gamma-induced transcripts, we defined 790 IRITs in isografts. IRITs were remarkably heterogeneous in timing and mechanisms. Some were increased in host as well as donor kidneys, reflecting systemic influences (wounding, anesthetic). Most reflected local stress, resembling changes in ATN despite the lack of ATN histopathology. Mathematical decomposition of IRIT expression patterns confirmed heterogeneity, separating IRIT changes into component subsets, with an early peak (day 1) showing systemic effects and late peaks that resembled ATN, manifested Tgf-ss1 effects and recapitulated embryonic development. In allografts IRITs were initially similar to isografts but diverged due to allogeneic injury. The allospecific induction of IRITs was T-cell-dependent but perforin-granzyme-independent, compatible with delayed type hypersensitivity. The alloresponse strikingly and selectively increased the late IRITs but not the IRITs that peak early, indicating that rejection triggers parenchymal responses similar to those in ATN.