Novel lncRNA‐prader willi/angelman region RNA, SNRPN neighbour (PWARSN) aggravates tubular epithelial cell pyroptosis by regulating TXNIP via dual way in diabetic kidney disease

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 lentivirus‐mediated 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. CONCLUSIONS: These findings illustrate distinct dual molecular mechanisms for PWARSN‐modulated TXNIP and PTECs pyroptosis in DKD, presenting PWARSN as a promising therapeutic target for DKD.