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Kidney Week

Abstract: PO0918

RNA-Binding Proteins Tristetraprolin and Human Antigen R Are Novel Modulators of Podocyte Injury in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Guo, Jia, Zhengzhou University First Affiliated Hospital, Zhengzhou, Henan, China
  • Gong, Rujun, The University of Toledo, Toledo, Ohio, United States
  • Liu, Zhangsuo, Zhengzhou University First Affiliated Hospital, Zhengzhou, Henan, China
Background

Diabetic kidney disease (DKD) is one of the most common complications of diabetes and the most common cause of end-stage renal disease, with no definitive therapy yet available to halt its progression. As key RNA-binding proteins (RBP) that play a pivotal role in epigenetic regulation, Tristetraprolin (TTP) and human antigen R (HuR) competitively bind to mRNAs of myriad cytokines, exert opposite effects on RNA stability, and dictate overall inflammatory states. However, the roles of these RBP in diabetes-related glomerulopathy is poorly understood. Herein, we investigated whether and how TTP and HuR are involved in the posttranscriptional regulation of podocytopathic molecules and inflammatory cytokines in DKD.

Methods

Kidney tissues were procured from diabetic patients and from db/db mice. Quantitative RT-PCR was performed to measure mRNA expression levels of IL-17 and claudin-1. Lentivirus vector transduction was employed to overexpress or silence target proteins. RNA immunoprecipitation (RIP) and co-immunoprecipitation assays were used to identify RNA-protein and protein-protein interactions.

Results

In DKD patients and db/db mice, TTP expression was significantly decreased and HuR expression was increased in glomerular podocytes, concurrent with podocyte injury, histological signs of DKD, and augmented glomerular expression of interleukin (IL)-17 and claudin-1, which are targets of TTP and HuR, as evidenced by RNA immunoprecipitation. In cultured podocytes, exposure to high ambient glucose amplified HuR expression and repressed TTP expression, upregulated IL-17 and claudin-1, and promoted podocyte injury. Thus, TTP hypoactivity or HuR hyperactivity is sufficient and essential to diabetic podocytopathy. Moreover, in silico analysis revealed that several kinases govern phosphorylation and activation of TTP and HuR, and glycogen synthase kinase (GSK)-3β activated both TTP and HuR, which harbor putative GSK-3β consensus phosphorylation motifs.

Conclusion

TTP and HuR are dysregulated in DKD via a GSK3b-mediated mechanism and play crucial roles in podocyte injury via posttranscriptional regulation of diverse molecules implicated in inflammation and podocytopathy. Our findings provide novel insights into the mechanism of and identify therapeutic targets for diabetic kidney disease.

Funding

  • Government Support - Non-U.S.