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 + doublepositive 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 was positively correlated with TGF-β1 and collagen-I. We also showed that RIP1/3 or MLKL inhibitors decreased the expression of RIP3, MLKL, TGF-β1, and Smad3 in HK-2 cells treated with TNF-α. FGF-2, α-SMA, Vimentin and FN were overexpressed in the hRIFs cultured with the supernatant of necroptotic HK-2 cells, whereas necroptosis blockers (Nec-1s, GSK'872 and NSA) and TGF-β1/Smad3How to cite this article: Lin Z, Chen A, Cui H, et al. Renal tubular epithelial cell necroptosis promotes tubulointerstitial fibrosis in patients with chronic kidney disease.
Background Hippocampal alterations have been implicated in the pathophysiology of cognitive impairment in hemodialysis patients. The hippocampus consists of several distinct subfields, and the molecular mechanisms underlying cognition might be associated with specific hippocampal subfield volume changes. However, this has not yet been investigated in hemodialysis patients. This study aimed to explore volumetric abnormalities in hippocampal subfields in regular hemodialysis patients. Methods High-resolution T1-weighted structural images were collected in 61 subjects including 36 hemodialysis patients and 25 healthy controls. A state-of-the-art hippocampal segmentation approach was adopted to segment the hippocampal subfields. Group differences in hippocampal subfield volumes were assessed in Python with a statsmodels module using an ordinary least squares regression with age and sex as nuisance effects. Results Hemodialysis patients had significantly smaller volumes in the bilateral hippocampus (p < 0.05/2, Bonferroni corrected), CA (cornu ammonis) 1, CA4, granule cell and molecular layer of the dentate gyrus, hippocampus-amygdala-transition-area and molecular layer of the hippocampus than healthy controls (p < 0.05/24, Bonferroni corrected). Hemodialysis patients also had lower volumes in the left hippocampal tail and right fimbria than healthy controls (p < 0.05/24, Bonferroni corrected). Hippocampal subfield volumes were associated with neuropsychological test scores, the duration of disease and hemoglobin levels. Conclusions We found smaller hippocampal subfield volumes in hemodialysis patients, which were associated with impaired cognition, supporting their role in memory disturbance in the hemodialysis population. However, multiple clinical factors may have confounded the results, and therefore, the interpretation of these results needs to be cautious.
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