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

被引：17

作者：

Wang, Xiangyu ^{[1
]}

Song, Minkai ^{[2
]}

Li, Xiaomin ^{[1
]}

Su, Cailin ^{[1
]}

Yang, Yanlin ^{[1
]}

Wang, Kai ^{[3
]}

Liu, Cuiting ^{[4
]}

Zheng, Zongji ^{[1
]}

Jia, Yijie ^{[1
]}

Ren, Shijing ^{[1
]}

Dong, Wenhui ^{[1
]}

Chen, Jiaqi ^{[1
]}

Wang, Ting ^{[5
]}

Liu, Lerong ^{[1
]}

Guan, Meiping ^{[1
]}

Zhang, Chao ^{[5
]}

Xue, Yaoming ^{[1
]}

机构：

[1] Southern Med Univ, Nanfang Hosp, Dept Endocrinol & Metab, Guangzhou, Peoples R China

[2] Southern Med Univ, Nanfang Hosp, Dept Orthopaed, Div Orthopaed Surg, Guangzhou, Peoples R China

[3] Southern Med Univ, Nanfang Hosp, Dept Gen Surg, Div Hepatobiliopancreat Surg, Guangzhou, Peoples R China

[4] Southern Med Univ, Cent Lab, Guangzhou, Peoples R China

[5] Southern Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Guangdong Prov Key Lab Single Cell Technol & Appli, Guangzhou, Peoples R China

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2023年 / 325卷 / 02期

关键词：

ceramide synthase 6; diabetic kidney disease; interstitial fibrosis; mitophagy; renal tubular epithelial cell; METABOLISM; SPHINGOLIPIDS;

D O I：

10.1152/ajpcell.00144.2023

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：C538 / C549

页数：12

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