Long noncoding RNA ENST00000458139 promotes mitochondrial dysfunction and apoptosis of podocytes in diabetic kidney disease through binding with SNRPA1

Diabetic kidney disease (DKD) is recognized as 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 evidence has reported that long Noncoding RNAs (lncRNAs) exert a vital role in DKD; however, their 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 compared with healthy controls. However, its function and detailed molecular mechanisms in DKD are completely undefined. In this study, we found that lnc458 was significantly increased in patients with DKD and high-glucose-induced podocytes. We revealed that the upregulation of lnc458 was associated with the severity of DKD. Gain- and loss-of-function experiments suggested silence of lnc458 alleviated high glucose-induced mitochondrial dysfunction and apoptosis in podocytes, while overexpression of lnc458 in podocytes led to an opposite result. Subsequently, we performed a biotin-labeled RNA pull-down followed by mass spectrometry to screen for potential lnc458-binding proteins and to identify the putative targets of lnc458 using RNA-seq. Mechanistically, we demonstrated that lncRNA ENST00000458139 facilitated podocyte injury via SNRPA1-mediated MYC transactivation, leading to upregulation of DDIT4 and mitochondrial dysfunction and apoptosis in podocytes. Collectively, our findings highlight a novel pathogenesis in podocyte injury and pave the way for developing a prospective therapeutic strategy for treating DKD. Lnc458 facilitates the expression of DDIT4 via SNRPA1-Mediated MYC Transactivation resulting in the mitochondrial dysfunction and podocytes injury, and then promoting the progression of DKD. • LncRNA ENST00000458139 upregulated in DKD patients and correlated with the severity of DKD. • Silence of ENST00000458139 Alleviated High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes. • ENST00000458139 Physically Interacts with SNRPA1 to increases MYC Target Gene DDIT4 Expression in Podocytes. • ENST00000458139 Facilitates Mitochondrial Dysfunction and Apoptosis of podocytes via SNRPA1-Mediated MYC Transactivation.