Endoplasmic reticulum (ER) stress is involved in the process of kidney fibrosis. Spliced X-box binding protein 1 (XBP1S) is the key mediator of ER stress while its role in fibrosis is still poorly understood. This study was aimed to investigate the role of XBP1S in renal fibrosis and evaluate whether valsartan could alleviate fibrosis through XBP1S. Renal interstitial fibrosis was induced by unilateral ureteral obstruction (UUO) in C57BL/6 mice, and UUO mice were daily administered with valsartan (20 mg/kg) through oral gavage. After 7 days of UUO, at euthanasia, left kidney was collected to examine the histological alteration by using haematoxylin-eosin staining, Masson's trichrome staining, Sirius red staining and immunohistochemistry. Western blot was used to assess XBP1S, targets of XBP1S, fibronectin, α-SMA, BAX and BCL2 protein levels. Real-time polymerase chain reaction was performed to assess NADPH oxidase subunits p47-phox and p67-phox mRNA levels. The results showed that XBP1S expression was decreased by about 70% in the UUO mice compared with that in sham mice (P < 0.01), which was reversed by valsartan administration (P < 0.05). Meanwhile, UUO-induced renal interstitial fibrosis was attenuated by valsartan treatment. In addition, the protein levels of fibronectin and α-SMA were upregulated by UUO induction (P < 0.01), and valsartan administration inhibited the protein levels of fibronectin and α-SMA in UUO mice (P < 0.05). Western blot analysis showed that the ratio of BAX to BCL2 protein level was increased in UUO model compared with that in sham mice, and the increment also was diminished by valsartan treatment (P < 0.05). Finally, UUO-induced mRNA levels of p47-phox and p67-phox were significantly attenuated by valsartan administration (P < 0.05). These results showed that valsartan at least partly restores renal interstitial fibrosis by enhancing XBP1S activation through inhibiting oxidative stress and apoptosis in the UUO mice. These results suggest that XBP1S could be a potential therapeutic target for kidney fibrosis.
Animals ; Apoptosis ; Fibronectins ; Fibrosis ; Kidney ; Kidney Diseases ; Mice ; Mice, Inbred C57BL ; NADPH Oxidases ; Oxidative Stress ; Phosphoproteins ; Real-Time Polymerase Chain Reaction ; Ureteral Obstruction ; X-Box Binding Protein 1

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China