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Abstract: FR-OR37

Long Noncoding RNA (lncRNA) PVT1 Induces Mitochondrial Damage and Inflammation via TRIM56 in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Lv, Zhimei, Shandong Provincial Hospital, Jinan, Shandong, China
  • Wang, Ziyang, Shandong Provincial Hospital, Jinan, Shandong, China
  • Wang, Rong, Shandong Provincial Hospital, Jinan, Shandong, China
Background

Diabetic kidney disease (DKD), one of the chronic microvascular complications of diabetes mellitus (DM), is the leading inducement of end stage renal disease (ESRD) globally, and increasing number of studies have demonstrated that immunity and inflammation are key pathogenic mechanisms in DKD. Notably, hyperglycemia-induced mitochondrial dysfunction played a pivotal role in activating innate immunity. However, the concrete mechanisms responsible for mitochondrial damage and inflammation of podocytes during DKD remain poorly understood.

Methods

The role of PVT1 was investigated by resorting to cultured podocytes, podocyte-specific deletion of Pvt1 (Nphs2-Cre/Pvt1flox/flox) mice and human samples. RT-qPCR, western blotting, RNA-FISH, TEM, histology staining, immunofluorescence, RIP, MeRIP, RNA pull-down, luciferase reporter assays, and Seahorse XF Cell Mito Stress Test were utilized for mechanistic study of the interaction between PVT1, TRIM56 and AMPKα further.

Results

We observed a significant upregulation of long non-coding RNA (lncRNA) PVT1 in plasma of patients with DKD. And we generated mice with podocyte-specific deletion of Pvt1 (Nphs2-Cre/Pvt1flox/flox) and confirmed that PVT1 deletion ameliorated diabetes-induced podocyte injury, glomerular pathology and proteinuria. We further demonstrated a novel role of PVT1 in regulating podocyte mitochondrial dysfunction and inflammation through TRIM56-mediated cGAS-STING signaling pathway. Similar results were validated in podocyte-specific deletion of Trim56 (Nphs2-Cre/Trim56flox/flox) in DKD mice models. Mechanistically, PVT1 was upregulated due to m6A demethylation under hyperglycemia conditions, and the stabilized PVT1 involved in mitochondrial dysfunction by interacting with TRIM56 post-transcriptionally to manipulate the ubiquitination of AMPKα, which subsequently induced mitochondrial injury. Meanwhile, the cytosolic mtDNA, released from damaged mitochondria, was recognized by the cGAS-STING pathway, linking mitochondrial homeostasis disruption to inflammatory responses in podocytes. Moreover, TRIM56 could catalyze STING in a ubiquitous manner to mediate inflammation directly in podocytes under high glucose environment.

Conclusion

Our study proposes the important role of PVT1 and TRIM56 in mitochondrial damage and inflammation, providing a potential therapeutic target against DKD.

Funding

  • Government Support – Non-U.S.