Kidney Week

Abstract: FR-PO690

YBX1 Alleviated Kidney Injury as a "Reader" of m5C Methylation in Adriamycin-Induced FSGS Mice

Session Information

• Glomerular Diseases: From Inflammation to Fibrosis - II
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

• Zhou, Hua, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

Hua Zhou,

• Kopp, Jeffrey B., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States

Jeffrey B. Kopp,

• Feng, Zixuan, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

Zixuan Feng,

• Miao, Feifei, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

Feifei Miao,

• Jiao, Congcong, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

Congcong Jiao,

• Ma, Cong, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

Cong Ma,

• Zhang, Yonghe, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

Yonghe Zhang,

• Luan, Junjun, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China

Junjun Luan,

Background

Focal segmental glomerulosclerosis (FSGS) is a common cause of adult nephrotic syndrome. Currently, effective treatments lack due to unclear understanding of its pathogenesis. Recently, Y-box binding protein 1 (YBX1) has been found as a 5 methylcytosine (m5C) ‘reader’ to stabilize mRNA and promote protein translation. However, the role of YBX1 in FSGS remains unknown.

Methods

FSGS was induced by adriamycin (ADR) in BALB/c mice. Adeno-associated virus 9 (AAV9) containing YBX1 was delivered to FSGS mice for overexpressing YBX1. Mice (n=24) were randomly divided into four groups: normal control (NC), ADR, ADR + AAV9-control, and ADR + AAV9-YBX1. Urine protein creatinine ratio (UPCR), serum creatinine (Scr), and blood urea nitrogen (BUN) were examined by biochemistry. Histological damages were evaluated by PAS and Masson staining and transmission electron microscopy (TEM). YBX1; podocyte biomarkers WT1, synaptopodin, and podocin; profibrotic proteins α-smooth muscle actin (α-SMA), vimentin, and fibronectin (FN) were analyzed by Western blotting and immunofluorescence (IF) staining. The synaptopodin and YBX1 were double stained by fluorescence in situ hybridization and IF. Finally, these proteins were stained in renal biopsies from FSGS patients and NC kidneys.

Results

In FSGS mice, UPCR, BUN, and Scr were increased; WT1, synaptopodin, podocin were decreased; α-SMA, vimentin, and FN were overproduced. Importantly, renal YBX1 was decreased. In YBX1 overexpressed FSGS mice, UPCR, Scr, and BUN levels were improved. Meanwhile, the percentage of sclerotic glomeruli was decreased on PAS and Masson. The degree of foot processes fusion was alleviated under TEM. The levels of podocytic WT1, synaptopodin, and podocin as well as profibrotic α-SMA, vimentin, and FN were reverted by delivering YBX1. The co-localization of synaptopodin mRNA and YBX1 protein was shown in the cytoplasm of podocytes. The same change directions of podocytotic and profibrotic proteins were seen in renal biopsies from FSGS patients compared to NC kidneys.

Conclusion

YBX1 may play an important role in pathogenesis of FSGS by regulating synaptopodin mRNA and further alleviating glomerulosclerosis through serving as a m⁵C ‘reader’. YBX1 might be a novel therapeutic target for FSGS.

Funding

• Government Support – Non-U.S.