Renal tubular epithelial cell necroptosis promotes tubulointerstitial fibrosis in patients with chronic kidney disease

作者：Ziyan Lin, Ai Chen, Hongwang Cui, Ruihua Shang, Tian Su, Xiaoyan Li, Kekun Wang, Jing Yang, Keli Gao, Jie Lv, Jie Shen, Shanzhi Wang, Yonghui Qi, Minghao Guo, Yongjun Zhu · 发表于：The FASEB Journal · 年份：2022 · DOI：10.1096/fj.202200706rr · 被引用次数：33 · 研究领域：Renal and related cancers、Chronic Kidney Disease and Diabetes

Abstract Renal fibrosis, a common pathological manifestation of virtually all types of chronic kidney disease (CKD), ultimately predisposes patients to end‐stage renal disease. However, there is no effective therapy for renal fibrosis. Our earlier studies proved that RIP3‐mediated necroptosis might be an important mode of renal tubular cell death in rats with chronic renal injury. Under transmission electron microscopy (TEM), we found morphological changes in the necrosis of human renal tissue, and the percentage of necrotic cells increased significantly in patients with stages 2 and 3a CKD. Immunofluorescence analyses showed that the percentages of TUNEL + /RIP3 + double‐positive and TUNEL + /MLKL + double‐positive tubular epithelial cells in renal tubules of patients with stages 2 and 3a CKD were significantly increased compared to those in control patients without renal disease. Immunohistochemistry analyses of renal biopsy specimens from patients with CKD revealed RIP3, MLKL, and p‐MLKL upregulation in patients with stages 2 and 3a CKD, suggesting that necroptosis of renal tubular epithelial cells in CKD patients occurs, and the peak of necroptosis was in stages 2 and 3a CKD. We showed that profibrotic factor proteins (TGF‐β1, Smad2 and Smad3) and fibroblast activation markers (α‐SMA and Vimentin) were specifically upregulated in stage 2 and 3a CKD patients. In addition, Pearson correlation analysis showed that the percentage of necroptotic renal tubular epithelial cells ...