LncRNA Gm13561 interacts with the splicing factor Hnrnpa1 to safeguard podocytes from apoptosis and oxeiptosis in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus, without suitable therapies, ultimately leading to end-stage renal disease. Podocyte loss serves as an initial insult during DN progression, yet the endogenous protective mechanisms remain elusive. Our single-nucleus RNA sequencing data revealed a large group of differentially expressed lncRNAs in renal tissues of DN. In this study, we found that Gm13561 was a podocyte-specific lncRNA predominantly localized in the nucleus and significantly downregulated in both DN mouse renal tissues and high-glucose-induced mouse podocytes. Gain- and loss-of-function studies demonstrated that overexpression of Gm13561 attenuated high-glucose-induced podocyte apoptosis, ROS accumulation, and oxeiptosis, while knockdown of Gm13561 aggravated these phenotypes under normal glucose conditions. Mechanistically, RNA pull-down coupled with mass spectrometry was performed and identified that Gm13561 interacts with the splicing factor Hnrnpa1. RNA immunoprecipitation assay further validated their binding association. Intriguingly, Hnrnpa1 knockdown abolished the protective effects of Gm13561 against apoptosis and oxeiptosis, and vice versa. Furthermore, RNA sequencing revealed that Gm13561 and Hnrnpa1 co-regulated alternative splicing of 446 overlapping genes, with 25 genes enriched in ROS-related and apoptotic pathways. These results together suggested a novel regulatory axis between Gm13561 and Hnrnpa1 that safeguards podocytes from apoptosis and oxeiptosis via modulating alternative splicing, and may serve as a potential therapeutic target for DN.