Decoy receptor 2 mediates the apoptosis-resistant phenotype of senescent renal tubular cells and accelerates renal fibrosis in diabetic nephropathy

Abstract

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 role of this phenotype in diabetic nephropathy (DN) remain unclear. Our previous study was the first to demonstrate that decoy receptor 2 (DcR2) is associated with apoptotic resistance in senescent RTECs and renal fibrosis. In this study, we aimed to further explore the mechanism of DcR2 in apoptosis-resistant RTECs and renal fibrosis in DN. DcR2 was co-localized with fibrotic markers (α-SMA, collagen IV, fibronectin), senescent marker p16, and antiapoptotic proteins FLIP and Bcl2 but rarely co-localized with caspase 3 or TUNEL. DcR2 overexpression promoted renal fibrosis in mice with streptozotocin (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 (caspases 8 and 3) in senescent RTECs, resulting in apoptotic resistance. In contrast, DcR2 knockdown produced the opposite effects in vitro and in vivo. Moreover, quantitative proteomics and co-immunoprecipitation experiments demonstrated that DcR2 interacted with glucose-related protein 78 kDa (GRP78), which has been shown to promote apoptotic resistance in cancer. GRP78 exhibited co-localization with senescent and antiapoptotic 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. Thus, 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.

Cell senescence-associated genes predict the malignant characteristics of glioblastoma

“…During embryogenesis and tissue remodeling, senescent process is required [ 38 ]. And senescent cells usually exhibit biological processes or biological pathways associated with senescent, including accumulation of lipofuscin, DNA damage foci, secretion of a large number of factors which were known as the senescence-associated secretory phenotype (SASP) and other changes [ 39 – 42 ]. It has been demonstrated that senescence can arrest tumor progression and can occur in different types of tumor cells [ 43 , 44 ].…”

Cellular senescence of renal tubular epithelial cells in acute kidney injury

“…Both mRNA and protein levels of Bcl-W and Bcl-xL are upregulated in senescent cells, highlighting the pivotal role of the BCL-2 protein family in apoptosis resistance among senescent cells [ 21 , 22 ]. Recent studies have revealed that the decoy receptor DcR2 is upregulated in senescent cells, and it functions to inhibit apoptosis in senescent fibroblasts and RTECs [ 23 , 24 ]. Furthermore, p21 can inhibit apoptosis in senescent cells by suppressing the JNK and caspase signaling pathways [ 25 ].…”

“…Conversely, downregulation of DcR2 expression promotes NK cell clearance of senescent cells, thereby inhibiting liver fibrosis [ 171 ]. In the context of senescent RTECs, inhibiting DcR2 expression has been observed to promote apoptosis, reduce SASP secretion, and inhibit renal interstitial fibrosis [ 24 ]. These findings suggest that promoting apoptosis in senescent RTEC may represent an effective approach for improving AKI prognosis.…”