Severe ischemia and reperfusion injury induces epigenetic inactivation of LHX1 in kidney progenitor cells after kidney transplantation.

Abstract

Severe ischemia-reperfusion injury (IRI) causes acute and chronic kidney allograft damage. As therapeutic interventions to reduce damage are limited yet, research on how to promote kidney repair has gained significant interest. To address this question, we performed genome-wide transcriptome and epigenome profiling in progenitor cells isolated from urine of deceased (severe IRI) and living (mild IRI) donor human kidney transplants and identified LIM homebox-1 (LHX1) as an epigenetically regulated gene whose expression depends on the IRI severity. Using a mice model of IRI, we observed a relationship between IRI severity, LHX1 promoter hypermethylation and LHX1 gene expression. By functional studies we confirmed that LHX1 expression is involved in proliferation of epithelial tubular cells and podocyte differentiation from kidney progenitor cells. Our results provide evidence that severe IRI may reduce intrinsic mechanisms of kidney repair through epigenetic signaling.