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Abstract：
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 ceramide synthase 6 (Cers6) 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. Cers6 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 PINK1 expression in CERS6 knockdown HK-2 cells diminished the therapeutic effect of CERS6 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.NEW & NOTEWORTHY This article addresses the roles of ceramide synthase 6 (CERS6) and CERS6-derived ceramides in renal tubular epithelial cells of diabetic kidney disease (DKD) associated interstitial fibrosis. Results from knockdown of CERS6 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.
摘要：
在糖尿病肾病（DKD）期间，肾小管上皮细胞（RTEC）中的异位神经酰胺（CER）积累与间质纤维化和蛋白尿有关。由于RTEC主要负责肾脏能量代谢，它们的功能与线粒体质量控制密切相关。尚未彻底研究CER合成在糖尿病肾纤维化进展中的作用。在这项研究中,我们观察到在db/db小鼠的肾皮质中神经酰胺合酶6（CERS6）表达的显着上调，与Cer6增加的CER(d18:1/14:0)和CER(d18:1/16:0)的产量一致。同时,RTEC中受损线粒体的数量增加。Cers6缺乏减少了肾脏皮质中CER（d18：1/14：0）和CER（d18：1/16：0）的异常积累，在RTECs中恢复PTEN诱导的激酶1（PINK1）介导的线粒体自噬，并导致DKD中线粒体受损减少和间质纤维化减弱。自动对接分析表明，CER（d18：1/14：0）和CER（d18：1/16：0）均可与PINK1蛋白结合。此外，抑制CERS6敲低HK-2细胞中的PINK1表达降低了CERS6缺陷对DKD的治疗作用。总之,CERS6衍生的CER（d18：1/14：0）和CER（d18：1/16：0）可能通过与PINK1蛋白结合来抑制PINK1调节的线粒体自噬，从而加剧DKD肾间质纤维化的进展。
