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Chinese Journal of Nephrology ; (12): 23-30, 2021.
Article in Chinese | WPRIM | ID: wpr-885477


Objective:To investigate the number of necroptotic renal tubular epithelial cells in renal tissues of patients with chronic kidney disease (CKD) and the correlation with clinicopathologic parameters, and explore its role in the progression of the excessive loss of renal tubular cells and chronic kidney injury.Methods:Renal tissue samples from 60 patients (18-65 years old) with CKD proven by kidney biopsy in the First Affiliated Hospital of Hainan Medical University from June 2017 to June 2019 were collected. According to internationally accepted K/DOQI guidelines, the patients were divided into 1-4 stages of CKD, with 15 cases in each stage. The number of necroptotic renal tubular epithelial cells in patients with different stages of CKD was detected using receptor-interacting protein 3 (RIP3) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) fluorescent staining, and the expression of RIP3 and MLKL, marker protein of necroptosis, was detected by immunohistochemistry. Pearson correlation analysis was used to analyze the correlation between the percentage of necroptotic renal tubular epithelial cells and clinicopathologic parameters. In addition, the expression of angiotensinogen Ⅱ receptor (AT2R) in renal tissue and its correlation with the percentage of necroptotic renal tubular epithelial cells were analyzed.Results:With the development of CKD, the structural destruction of renal tubules in patients with CKD was gradually aggravated, and the renal tubules in the corresponding areas were atrophied, accompanied by worsening interstitial fibrosis. The adjacent renal tubules were focally dilated and numerous protein tubules were seen in the tubules. Importantly, renal tubular injury score in second and third stage of CKD was significantly higher than that in control group (both P<0.01). TUNEL+RIP3 immunofluorescence staining results showed that the percentage of TUNEL/RIP3 double positive renal tubular epithelial cells (necroptotic renal tubular epithelial cells) in renal tubules of the second and third stage of CKD was higher (all P<0.01). Immunohistochemical results showed that RIP3, MLKL and AT2R proteins were mainly expressed in cytoplasm of renal tubular epithelial cells, and the expression of RIP3, MLKL and AT2R in renal tubular epithelial cells was higher in the second and third stage of CKD patients (all P<0.05). Pearson correlation analysis showed that the percentage of necroptotic renal tubular epithelial cells was positively correlated with blood urea nitrogen ( r=0.514, P=0.003), serum creatinine ( r=0.507, P=0.019), serum cystatin C ( r=0.571, P=0.026), serum uric acid ( r=0.592, P=0.008), renal tubules injury score ( r=0.901, P<0.001), renal interstitial fibrosis index ( r=0.700, P=0.001) and the expression of AT2R protein in renal tissue ( r=0.715, P=0.001). Conclusions:As CKD progresses, necroptosis of renal tubular epithelial cells in CKD patients occurs. The necroptotic cell death may be an important factor leading to renal tubular epithelial cell excessive death and the progression of chronic kidney injury. Furthermore, necroptosis of renal tubular epithelial cells may be related to the high expression of AT2R in kidney tissue.

Acta Pharmaceutica Sinica B ; (6): 2768-2782, 2021.
Article in English | WPRIM | ID: wpr-888886


Pyroptosis is the process of inflammatory cell death. The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection. Excessive pyroptosis, however, leads to several inflammatory diseases, including sepsis and autoimmune disorders. Pyroptosis can be canonical or noncanonical. Upon microbe infection, the canonical pathway responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), while the noncanonical pathway responds to intracellular lipopolysaccharides (LPS) of Gram-negative bacteria. The last step of pyroptosis requires the cleavage of gasdermin D (GsdmD) at D275 (numbering after human GSDMD) into N- and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11 (caspase 4/5 in humans, caspase 11 in mice) in the noncanonical pathway. Upon cleavage, the N-terminus of GsdmD (GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1

Chinese Journal of Nephrology ; (12): 579-586, 2018.
Article in Chinese | WPRIM | ID: wpr-711141


Objective To evaluate the prevalence of chronic kidney disease (CKD) in Chinese adult health check-up population,and to compare with the prevalence of CKD in the study of the general population as well as the large CKD cross-sectional study in China.Methods Epidemiological studies about CKD in Chinese adults health check-up population from January 2007 to December 2017 were searched in PubMed,SinoMed,CNKI,VIP and Wanfang Data.Meta-analysis of the prevalence of CKD was performed with software of Stata 12.0.Subgroup analyses of CKD staging,urban and rural,as well as geographical areas of the general population were executed.Results Twenty-two studies from adult health check-up population were included (238 349 persons).Egger's regression showed no publication bias (P > 0.05).The unstandardized prevalence rate of CKD was 12.49% (male 12.8%,female 12.5%).The respective unstandardized prevalences of proteinuria,hematuria and eGFR decline were 5.90%,5.83% and 2.75%.The unstandardized prevalences of CKD in urban and rural population were 13.21% and 11.90%.The stages of CKD were mainly concentrated in the early stages.There was no significant difference in the non-standard detection rate of total eGFR decline among the adult medical examination population,the general population and the population studied cross-sectionally (P > 0.05).Furthermore,no significant difference in the non-standard detection rate of total hematuria and male hematuria was found between the adult health check-up population and the general population.In addition,the total proteinuric non-standard detection rate of the adult general population was similar with that of population studied cross-sectionally (P > 0.05).Conclusions The prevalence of CKD in Chinese adults is higher,the overall prevalence is however underestimated.The results of epidemiological investigation in adult health check-up population are similar to those of the general population,especially in men.

Chinese Journal of Pathophysiology ; (12): 1266-1272, 2016.
Article in Chinese | WPRIM | ID: wpr-496552


[ ABSTRACT] AIM: To explore whether autophagy is involved in the excessive death of renal tubular epithelial cells in subtotal nephrectomy ( SNx) rats and the relationship between autophagy and necroptosis in the kidney of SNx rats. METHODS:Male Sprague-Dawley rats were randomly assigned to control group ( n=6 ) and SNx group ( n=42 ) .The rats in SNx group were subjected to SNx.Sham surgery was performed in the rats in control group.The rats in SNx group were divided into subgroups at 0, 4, 8 and 12 weeks ( n=6) and the other rats in SNx group were divided into SNx+vehi-cle group, SNx+necrostatin-1 (Nec-1) group and SNx+3-methyladenine (3-MA) group.The expression of RIP1, RIP3, LC3 and beclin-1 at mRNA and protein levels was measured at 0, 4, 8 and 12 weeks by qPCR and immunohistochemistry. The effects of Nec-1 or 3-MA on the protein expression of LC3-I, LC3-II and beclin-1, and production of reactive oxygen species ( ROS) in the rat kidney were determined by Western blot and DCFH-DA staining.The death of renal tubular epi-thelial cells in the SNx rats was observed by TUNEL staining and electron microscopy.Finally, the effects of Nec-1 and 3-MA on blood urea nitrogen ( BUN) , serum creatinine ( SCr) and the pathological changes of the renal tissues were ana-lyzed.RESULTS:The highest mRNA and protein levels of RIP1, RIP3, LC3 and beclin-1 appeared at the 8th week after SNx (P cells were decreased in the SNx rats treated with Nec-1 and 3-MA (P<0.01), but 3-MA did not reduce the increased con-centration of ROS.In addition, treatment with Nec-1 and 3-MA obviously reduced BUN, SCr (P<0.05), glomeruloscle-rosis index and tubulointerstitial injury score (P<0.01).CONCLUSION:Autophagy participates in the excessive death of renal tubular epithelial cells in SNx rats.Inhibition of autograph prevents necroptotic cell death of renal tubular cells, and alleviates chronic renal injury in SNx rats.