Long Noncoding RNA ENST00000458139 Promotes Mitochondrial Dysfunction and Apoptosis of Podocytes in Diabetic Kidney Disease Through Binding with SNRPA1

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) and is related to progressive albuminuria, consequent to kidney destruction that involves podocyte mitochondrial dysfunction and apoptosis. Burgeoning evidences have reported that long noncoding RNA (lncRNA) exert a vital role in DKD, however, its mechanism is largely unknown. Previously, we performed RNA sequencing (GSE199838) in human DKD samples and identified that lncRNA ENST00000458139 (lnc458) was significantly upregulated in DKD patients. However, its function in DKD is completely undefined. Methods: RNA-Fluorescence in Situ Hybridization (RNA-FISH) and real-time PCR were performed to detect the expression of lnc458 in DKD. Spearman analysis were used to evaluate the correlation between lnc458 and kidney function. real-time PCR, Western blot, and immunofluorescence were performed to assess podocyte injury. Mitochondrial dysfunction and apoptosis were assessed via MitoSOX staining, JC-1 staining, and TUNEL assay. Biotin-labeled RNA pull-down, mass spectrometry analysis, transcriptome sequencing, and dual luciferase assay were used to explore the role and underlying mechanism of lnc458 in DKD podocyte injury. Results: Lnc458 was significantly increased in DKD patients and in podocytes induced by high glucose. The upregulation of lnc458 was associated with the severity of DKD. Silence of lnc458 alleviated high glucose-induced mitochondrial dysfunction and apoptosis in podocyte, while overexpression of lnc458 led to the opposite outcome. Mechanistically, lncRNA ENST00000458139 promote podocyte injury via SNRPA1-mediated MYC transactivation, resulting in upregulation of DDIT4 and mitochondrial dysfunction and apoptosis in podocytes. Conclusion: Our study identified, for the first time, a vital role of LncRNA ENST00000458139-SNRPA-MYC regulatory network in podocyte mitochondrial dysfunction and apoptosis in DKD, which will provide insights into the prevention and treatment of DKD in the future. Funding: Government Support – Non-U.S.