Kidney cell response to acute cardiorenal and isolated kidney ischemia-reperfusion injury

Acute cardiorenal syndrome (CRS) represents a critical intersection of cardiac and renal dysfunction with profound clinical implications. Despite its significance, the molecular underpinnings that mediate cellular responses within the kidney during CRS remain inadequately understood. We employed single nucleus RNA sequencing (snRNAseq) to dissect the cellular transcriptomic landscape of the kidney following in a translational model of CRS, cardiac arrest/cardiopulmonary resuscitation (CA/PCR) in comparison to ischemia reperfusion injury (IRI). In each dataset, we found that proximal tubule (PT) cells of the kidney undergo significant gene expression changes, with decreased expression of genes critically important for cell identity and function, indicative of dedifferentiation. Based on this, we created a novel score to capture the dedifferentiation state of each kidney cell population and found that certain epithelial cell populations, such as the PT S1 and S2 segments, as well as the distal convoluted tubule, exhibited significant dedifferentiation response. Interestingly, the dedifferentiation response in the distal nephron differed in magnitude between IRI and CA/CPR. Gene set enrichment analysis (GSEA) of PT response to IRI and CA/CPR revealed similarities between the two models and key differences, including enrichment of immune system process genes. Transcriptional changes in both mouse models of AKI highly correlated with a dataset of human biopsies from patients diagnosed with acute kidney injury (AKI). This comprehensive single nucleus transcriptomic profiling provides valuable insights into the cellular mechanisms driving CRS.