Dynamics of cell states and alternative splicing following kidney ischemia-reperfusion injury

Abstract

The progression of kidney damage in chronic kidney disease (CKD) involves multiple post-injury stages and complex cellular and molecular mechanisms that are not yet fully understood. In our study we set to characterize the dynamics of mRNA splicing following kidney injury. To this end, we analyzed publicly available bulk RNA-seq data covering nine time points following a kidney ischemia-reperfusion injury (IRI) mouse experiment. Using topic modeling we discerned five distinct temporal phases corresponding to the following cell states: "early injury response", "injury", "repairing", "failed recovery", and "healthy proximal tubule". Additionally, we discovered a set of genes that are alternatively spliced between selected time points associated with these cell states, some of which are related to injury, stress, EMT, and apoptosis. Finally, we found several putative splicing regulators that are differentially expressed between the different time points and whose binding motifs are enriched in the vicinity of alternatively spliced exons, indicating that they may play critical roles in mRNA splicing dynamics following kidney injury and repair. These findings enhance our understanding of the molecular mechanisms involved in kidney injury and repair, offering potential avenues for developing targeted therapeutic strategies for acute kidney injury (AKI) and its progression to CKD.