FADD phosphorylation contributes to development of renal fibrosis by accelerating epithelial-mesenchymal transition.

FADD, a classical apoptotic signaling adaptor, has recently been reported to exhibit a series of non-apoptotic functions. Here, we report that FADD may play a critical role in the development of renal fibrosis. Neutrophil infiltration in the renal interstitial part, glomerular mesangial cell proliferation, and base-membrane thickening were observed in FADD-D mice by H&E, PAS, and PASM staining. Immunofluorescence analysis revealed that macrophage infiltration was significantly enhanced in FADD-D mice. Renal fibrosis might be induced by IgA nephritis in FADD-D mice as evidenced by increased Ki67 and type IV collagen. Additionally, the levels of α-SMA, Fibronectin, and Vimentin were also found to be elevated. Mechanism study indicated that the TLR4/myD88/NF-κB signaling pathway was activated in FADD-D mice. Moreover, FADD phosphorylation activated the mTOR and TGF-β/Smad pathway and accelerated the process of epithelial mesenchymal transition. Further studies indicated that the TGF-β1 pathway was also activated and the process of EMT was accelerated in both FADD-disrupted HEK293 cells and FADD-deficient MES cells. Thus, we concluded that FADD phosphorylation could lead to IgA nephritis and eventually result in renal fibrosis. Taken together, our study provides evidence, for the first time, that FADD, especially in its phosphorylated form, has an effect on the development of renal fibrosis.Abbreviations: FADD: FAS-associated protein with death domain; DED: death effector domain; DD: death domain; CKD: chronic kidney disease; ECM: extracellular matrix; ESRD: end-stage renal disease; RRT: renal replacement therapy; H&E: hematoxylin and eosin; PASM: periodic acid silver methenamine.

Citation

Yan Lin, Fangfang Cai, Xiaoyang Wang, Yunwen Yang, Yongzhe Ren, Chun Yao, Xiaoxing Yin, Hongqin Zhuang, Zichun Hua. FADD phosphorylation contributes to development of renal fibrosis by accelerating epithelial-mesenchymal transition. Cell cycle (Georgetown, Tex.). 2023 Mar;22(5):580-595

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PMID: 36281535

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