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

Abstract

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.

Sleeve gastrectomy links the attenuation of diabetic kidney disease to the inhibition of renal tubular ferroptosis through down-regulating TGF-β1/Smad3 signaling pathway

“…Renal tubular epithelial injury was closely related to the renal injury, and the programmed cell death was crucial in this process [11]. To date, the major types of death in the tubular epithelial cells of DKD included apoptosis, necroptosis, and pyroptosis [31][32][33]. Serving as a new type of cellular death [34], ferroptosis has been recently reported in tubular injury in DKD [11].…”

An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory

“…In the majority of studies exploring diabetes and its chronic complications, a hyperglycemic exposure period of 48–72 h is typically considered representative of chronic hyperglycemia with long-term deleterious effects. This holds true for conditions such as DKD, DF, and diabetic cardiomyopathy (Hu et al 2024 ; Wang et al 2024 ; Li, et al 2024 ; Song et al 2023 ; Feng et al 2023 ). However, it is worth noting that the duration of exposure to high glucose, as well as the periods of exposure to normal glucose, vary significantly across studies examining metabolic memory.…”