CERS6-derived ceramides aggravate kidney fibrosis by inhibiting PINK1-mediated mitophagy in diabetic kidney disease.

During diabetic kidney disease (DKD), ectopic ceramide (CER) accumulation in renal tubular epithelial cells (RTECs) is associated with interstitial fibrosis and albuminuria. As RTECs are primarily responsible for renal energy metabolism, their function is intimately linked to mitochondrial quality control. The role of CER synthesis in the progression of diabetic renal fibrosis has not been thoroughly investigated. In this study, we observed a significant upregulation of () expression in the renal cortex of db/db mice, coinciding with increased production of CER (d18:1/14:0) and CER (d18:1/16:0) by Cer6. Concurrently, the number of damaged mitochondria in RTECs rose. deficiency reduced the abnormal accumulation of CER (d18:1/14:0) and CER (d18:1/16:0) in the kidney cortex, restoring the PTEN-induced kinase 1 (PINK1)-mediated mitophagy in RTECs, and resulting in a decrease in damaged mitochondria and attenuation of interstitial fibrosis in DKD. Automated docking analysis suggested that both CER (d18:1/14:0) and CER (d18:1/16:0) could bind to the PINK1 protein. Furthermore, inhibiting expression in knockdown HK-2 cells diminished the therapeutic effect of deficiency on DKD. In summary, CERS6-derived CER (d18:1/14:0) and CER (d18:1/16:0) inhibit PINK1-regulated mitophagy by possibly binding to the PINK1 protein, thereby exacerbating the progression of renal interstitial fibrosis in DKD. This article addresses the roles of () and CERS6-derived ceramides in renal tubular epithelial cells of diabetic kidney disease (DKD) associated interstitial fibrosis. Results from knockdown of adjusted the ceramide pool in kidney cortex and markedly protected from diabetic-induced kidney fibrosis in vivo and in vitro. Mechanically, CERS6-derived ceramides might interact with PINK1 to inhibit PINK1/Parkin-mediated mitophagy and aggravate renal interstitial fibrosis in DKD.