CD44 plays a key role in aggravating tubular cell apoptosis in renal ischemia-reperfusion injury through p65/ PGC-1a pathway

Acute kidney injury (AKI) is rapidly increasing and becomes a major of public health problem nowadays. However, its underlying mechanism has not been elucidated. Studies have shown that cluster of differentiation-44 (CD44) play a role in the pathological process of AKI. Nevertheless, the molecule mechanism has not been totally clarified. Herein, we found that CD44 is increased in renal tubules in ischemia-reperfusion injury (IRI)-induced AKI mice. Knockout of CD44 improved mitochondrial biogenesis and mitochondrial fatty acid oxidation (FAO), further protecting against renal tubular cell apoptosis and kidney injury. Conversely, ectopic expression of CD44 impaired mitochondrial function and FAO, which exacerbated the pathological process of AKI. Transcriptome sequencing revealed NF-?B p65 is highly responsible for this process. In vitro, we found that CD44 induced activation of NF-?B p65 via mitogen-activated protein kinase (MAPK) ERK1/2 and MAPK p38, further transcriptionally silencing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) promoters. As a result, downregulation of PGC-1a contributed to impairment of mitochondrial dysfunction and FAO, resulting in the deterioration of AKI. Our study found that inhibiting CD44 is a new potential therapeutic strategy for AKI through promoting mitochondrial biogenesis and FAO. The underlying mechanism is associated with MAPK/p65/ PGC-1a pathway. Overall design: To verify the potential mechanism by which CD44 aggravates AKI, we established IRI models and performed RNA-seq in WT and CD44KO mice. We compared the gene expression differences between the two groups and performed GSEA enrichment analysis