The worldwide prevalence of diabetes mellitus (DM) has rapidly increased over the past 30 years along with consequential increases in the prevalence of microvascular and macrovascular diabetes complications. 1-7 Among patients with type 1 or 2 DM, 30%-40% develop diabetic kidney disease (DKD), with ~50% subsequently progressing to end-stage kidney disease that is associated with a high mortality rate. [8][9][10][11] Several factors can enhance the pathogenetic pathways initiated and sustained in the kidney by elevated glucose levels in DKD. These include metabolic
Objectives: Elevated thioredoxin-interacting protein (TXNIP)-induced pyroptosis contributes to the pathology of diabetic kidney disease (DKD). However, the molecular mechanisms in dysregulated TXNIP in DKD remain largely unclear. Materials and methods: Transcriptomic analysis identified a novel long noncoding RNA-Prader Willi/Angelman region RNA, SNRPN neighbour (PWARSN)-which was highly expressed in a proximal tubular epithelial cell (PTEC) under high glucose conditions. We focused on revealing the functions of PWARSN in regulating TXNIP-mediated pyroptosis in PTECs by targeting PWARSN expression via lentivirusmediated overexpression and CRISPR-Cas9-based knockout in vitro and overexpressing PWARSN in the renal cortex by AAV-9 targeted injection in vivo. A number of molecular techniques disclosed the mechanisms of PWARSN in regulating TXNIP induced-pyroptosis in DKD. Results: TXNIP-NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and PTEC pyroptosis were activated in the renal tubules of patients with DKD and in diabetic mice. Then we explored that PWARSN enhanced TXNIP-driven PTECs pyroptosis in vitro and in vivo. Mechanistically, cytoplasmic PWARSN sponged miR-372-3p to promote TXNIP expression. Moreover, nuclear PWARSN interacted and facilitated RNA binding motif protein X-linked (RBMX) degradation through ubiquitination, resulting in the initiation of TXNIP transcription by reducing H3K9me3-enrichment at the TXNIP promoter. Further analysis indicated that PWARSN might be a potential biomarker for DKD. Yi Song and Feng Guo contributed equally to this work.Gui-jun Qin is the Lead Contact.
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