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Abstract: SA-PO234

Decoy Receptor 2 Mediates the Apoptosis-Resistant Phenotype of Senescent Renal Tubular Cells and Accelerates Renal Fibrosis in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Author

  • Chen, Jia, Army Medical Center of PLA, Chongqing, Chongqing, China
Background

Apoptotic resistance leads to persistent accumulation of senescent cells and sustained expression of a senescence-associated secretory phenotype, playing an essential role in the progression of tissue fibrosis. However, whether senescent renal tubular epithelial cells (RTECs) exhibit an apoptosis-resistant phenotype and the mechanism remain unclear.

Methods

A total of 241 DN patients diagnosed by biopsy in our hospital from January 2012 to December 2019 were included. The STZ-induced DN mouse model was constructed. DcR2-siRNA and DcR2 overexpression plasmids were transfected into the kidney using ultrasonic microbubble technology. TECs senescence was constructed by high glucose treatment. The co-localization of DcR2 and apoptosis-related markers (FLIP, Bcl-2, caspase-3, caspase-8, Tunel) and fibrotic markers (a-SMA, collagen IV, fibronectin) were analyzed. DcR2 interacting proteins were screened and analyzed by co-immunoprecipitation combined with quantitative proteomics in renal tissue from DN patients and TECs.

Results

DcR2 was co-localized with fibrotic markers, and anti-apoptotic proteins FLIP and Bcl2 but rarely co-localized with caspase 3 or TUNEL. DcR2 overexpression promoted renal fibrosis in mice with STZ-induced DN, as evidenced by augmented Masson staining and upregulated expression of fibrotic markers. DcR2 overexpression also enhanced FLIP expression while reducing the expression of pro-apoptotic proteins, resulting in apoptotic resistance. In contrast, DcR2 knockdown produced the opposite effects in vitro and in vivo. Moreover, quantitative proteomics demonstrated that DcR2 interacted with GRP78, which has been shown to promote apoptotic resistance in cancer. GRP78 exhibited co-localization with senescent and anti-apoptotic markers but was rarely co-expressed with caspase 3 or TUNEL. Additionally, GRP78 knockdown decreased the apoptosis resistance of HG-induced senescent RTECs with upregulated cleaved caspase 3 and increased the percentage of apoptotic RTECs. Mechanistically, DcR2 mediated apoptotic resistance in senescent RTECs by enhancing GRP78–caspase 7 interactions and promoting Akt phosphorylation.

Conclusion

DcR2 mediated the apoptotic resistance of senescent RTECs and renal fibrosis by interacting with GRP78, indicating that targeting the DcR2–GRP78 axis represents a promising therapeutic strategy for DN.