LncRNA ENST00000532153.1 alleviates podocyte injury by inhibiting PARP1-mediated PARylation of ATF3 in diabetic kidney disease

Podocyte injury is a key event in the progression of diabetic kidney disease (DKD), and the role of long noncoding RNAs (lncRNAs) in DKD and podocyte injury is emerging. RNA sequencing, fluorescence in situ hybridization and real-time PCR results revealed that the expression of the lncRNA ENST00000532153.1 (lncRNA 153) was downregulated in patients with DKD and correlated with clinical parameters. Moreover, the overexpression of lncRNA 153 mitigated podocyte injury caused by high glucose (HG) stimulation. Following RNA-pulldown and mass spectrometry analysis, KEGG enrichment analysis revealed that the lncRNA 153 binding protein is primarily involved in protein processing in the endoplasmic reticulum (ER). Poly (ADP-ribose) polymerase 1 (PARP1) was subsequently identified as the binding protein of lncRNA 153. PARP1, a marker protein for apoptosis, was found to be upregulated in the kidneys of patients with DKD. Knockdown of PARP1 in podocytes under HG conditions resulted in the inhibition of ER stress and apoptosis, leading to the alleviation of podocyte injury both in vitro and in vivo. Furthermore, this study revealed that activating transcription factor 3 (ATF3) is a novel protein that interacts with PARP1, and that the interaction between them is involved in the regulation of gene transcription. Mechanistic studies demonstrated that lncRNA 153 binds to PARP1, inhibiting its interaction with ATF3 and subsequently reducing the transcriptional activity of ATF3, ultimately alleviating podocyte injury in DKD by suppressing ER stress and apoptosis. Therefore, our study suggests that lncRNA 153 and PARP1 may be attractive therapeutic targets for DKD.