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Abstract: PO0903

Disruption of Long Non-Coding RNA MIAT Induces Mitotic Catastrophe of Podocyte in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wang, Ziyang, Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  • Hu, Jinxiu, Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  • Yu, Qun, Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  • Lv, Zhimei, Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
  • Wang, Rong, Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
Background

Diabetic nephropathy (DN) is becoming the principal inducement of end-stage renal disease (ESRD) worldwide. Importantly, mitotic catastrophe (MC) is characterized as impeded mitosis-linked cell death, which plays an essential role in expediting podocyte loss and detaching from glomerular basement membrane (GBM). The concrete mechanism of MC in podocyte injury and proteinuria, however, remains inadequately elucidated. In the current study, we demonstrated the biological function and underlying mechanism of a long noncoding RNA myocardial infarction-associated transcript (Lnc MIAT) in podocytes MC.

Methods

The role of MIAT was investigated by resorting to cultured podocytes, CRISPR/Cas9 MIAT knockout mice and human samples. Immunofluorescence, western bolt, Transwell assay, TEM and histology staining including PAS and Masson staining were performed to assess the lesion of podocytes. RNA-FISH, RIP and luciferase reporter assays were utilized for mechanistic study of the interaction between MIAT, miR-130b and Sox4 further. Moreover, apoptosis and cell cycle of podocytes were detected by flow cytometry and the expression of G2/M transition-related proteins (p21cip1/waf1, cyclin B and cdc2).

Results

MIAT is noticeably upregulated in HG-stimulated podocytes, STZ-induced mice and serum of DN patients, accompanied by higher creatinine production and significantly lower eGFRs values in clinical. And MIAT contributes to the proliferation, apoptosis, migration and G2/M arrest of podocytes, while depletion of MIAT significantly meliorates podocytes injury and albuminuria by restoring slit diaphragms (SD) integrity, attenuating foot processes effacement (FPE) and suppressing cyclin B/cdc2-mediated G2/M arrest. Mechanistic investigation reveals that MIAT not only elevates Sox4 protein expression and subsequently manipulates the ubiquitination and acetylation of p53, thereby stifling downstream factors cyclin B/cdc2 via enhancing p21cip1/waf1 activity, but also participates in crosstalk with Sox4 mRNA through competition for miR-130b binding.

Conclusion

Our findings provide plausible insight in the interplay between LncRNA MIAT, miR-130b and Sox4 which consequently lead to podocyte mitotic dysfunction involved in the progression of DN, indicating MIAT may act as a promising biomarker and therapeutic target for DN patients.

Funding

  • Government Support - Non-U.S.