Inhibition of Drp1-mediated mitochondrial fission improves contrast-induced acute kidney injury by targeting the mROS-TXNIP-NLRP3 inflammasome axis.

Acute kidney injury (AKI) is a critical complication known for their extremely high mortality rate and lack of effective clinical therapy. Disorders in mitochondrial dynamics possess a pivotal role in the occurrence and progression of contrast-induced nephropathy (CIN) by activating NLRP3 inflammasome. The activation of dynamin-related protein-1 (Drp1) can trigger mitochondrial dynamic disorders by regulating excessive mitochondrial fission. However, the precise role of Drp1 during CIN has not been clarified. In vivo experiments revealed that inhibiting Drp1 through Mdivi-1 (one selective inhibitor of Drp1) can significantly decrease the expression of p-Drp1 (Ser616), mitochondrial p-Drp1 (Ser616), mitochondrial Bax, mitochondrial reactive oxygen species (mROS), NLRP3, caspase-1, ASC, TNF-α, IL-1ß, interleukin (IL)-18, IL-6, creatinine (Cr), malondialdehyde (MDA), blood urea nitrogen (BUN), and KIM-1. Moreover, Mdivi-1 reduced kidney pathological injury and downregulated the interaction between NLRP3 and thioredoxin-interacting protein (TXNIP), which was accompanied by decreased interactions between TRX and TXNIP. This resulted in increasing superoxide dismutase (SOD) and CAT activity, TRX expression, up-regulating mitochondrial membrane potential, and augmenting ATP contents and p-Drp1 (Ser616) levels in the cytoplasm. However, it did not bring impact on the expression of p-Drp1 (Ser637) and TXNIP. Activating Drp-1though Acetaldehyde abrogated the effects of Mdivi-1. In addition, the results of in vitro studies employing siRNA-Drp1 and plasmid-Drp1 intervention in HK-2 cells treated with iohexol were consistent with the in vivo experiments. Our findings revealed inhibiting Drp1 phosphorylation at Ser616 could ameliorate iohexol -induced acute kidney injury though alleviating the activation of the TXNIP-NLRP3 inflammasome pathway.

HMGB1-TLR4-IL-23-IL-17A axis accelerates renal ischemia-reperfusion injury via the recruitment and migration of neutrophils.

Renal ischemia-reperfusion injury (IRI) is an important cause of setting off acute kidney injury. Neutrophil-mediated immunomodulation has a pivotal role in the evolving of IRI. The HMGB1-TLR4-IL-23-IL-17A axis gives rise to neutrophil activation. Therefore, in the study, the role of the HMGB1-TLR4-IL-23-IL-17A axis in IRI was evaluated. Cell viability, inflammation, apoptosis, oxidative stress, survival, renal function and pathology, and the activation of macrophages and neutrophils were measured. Moreover, we evaluated the acetylation, translocation, and secretion of HMGB1 as well as levels of TLR-4, IL-23, IL-17A, and neutrophil chemokines (KC, LIX, and MIP-2). In vivo, anti-HMGB1 antibody decreased the acetylation, translocation, and secretion of HMGB1, reduced the expression of TLR-4, IL-23, IL-17A, KC, LIX, and MIP-2, alleviated the activation of macrophages and neutrophils, improved the survival rate and renal dysfunction, and decreased inflammation, apoptosis, oxidative stress, and pathological injury of the kidney. However, the intervention with recombinant HMGB1(R-HMGB1) significantly abolish the above effect of anti-HMGB1 in IRI. Neutralization IL-23 or IL-17A can alleviated the neutrophils mediated renal dysfunction by suppressing inflammation, apoptosis, and oxidative stress in IRI. In vitro, we confirmed that hypoxic/deoxygenation (H/R) induces the secretion of HMGB1 though acetylation on HK-2 and HMGB1 promotes the secretion of IL-23 in a HMGB1/TLR-4-dependent manner on macrophages. Together, these results implied that the HMGB1-TLR4-IL-23-IL-17A axis regulates inflammation, oxidative stress, apoptosis, and renal injury in IRI by promoting the recruitment and migration of neutrophils.

Clinical characteristics of 31 hemodialysis patients with 2019 novel coronavirus: a retrospective study.

AIM: Novel coronavirus pneumonia (COVID-19) has become pandemic. It brings serious threat to hemodialysis (HD) patients. Therefore, we carried out a study on the clinical characteristics of HD patients with COVID-19. METHODS: We retrospectively analyzed the data of 31 HD patients with COVID-19. The clinical features of patients include epidemiology, clinical symptoms, laboratory and imaging test, treatment and prognosis. RESULTS: 61.3% were severe, and 38.7% were mild. 83.9% had a close contact history with COVID-19 patients. The average age was 62.3 years comprising of 58.1% men and 41.9% women. Ninety percent had chronic diseases except ESRD. Clinical symptoms include cough (85%), fever (43%), and shortness of breath (48.4%), etc. Complications included ARDS (25.8%), AHF (22.6%), and septic shock (16.1%), etc. 64.5% of patients had remission, and 35.5% of patients had no remission with 6.5% deaths. Compared with the baseline before infection, HD patients with COVID-19 had lower lymphocytes, albumin and glucose, and higher D-dimer, albumin, phosphorus, lactate dehydrogenase, and CRP. There was no significant correlation between the neutrophils/lymphocytes ratio and the severity of the disease. CONCLUSIONS: Compared with the reported general population, the HD patients are susceptible to COVID-19 infection, especially older men and those with other underlying diseases. Moreover, HD patients have more severe infection and inflammation with less symptoms and worse outcome. COVID-19 infection can cause dialysis patients lower immunity, stronger inflammation, malnutrition, and internal environment disorder. Neutrophils/lymphocytes ratio does not reflect the severity of the HD patients with COVID-19.

Prevalence and associated factors of depressive symptoms among chronic kidney disease patients in China: Results from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE).

OBJECTIVE: Depression is the most common mental disorder in patients with chronic kidney disease (CKD), and previous studies have found that: (a) depression can accelerate the progression of CKD; and (b) depression is an independent risk factor for hospitalization and death among patients with CKD. Therefore, the objective of the current study was to investigate the prevalence of depression in Chinese patients with CKD, and to identify variables associated with depression. METHODS: The study analyzed baseline data from a multicenter prospective cohort study of Chinese patients with chronic kidney disease (the C-STRIDE study). In all, 2995 participants in CKD stages 1 to 4 who completed a survey of depressive symptoms were included in the analyses. Depressive symptoms were assessed by the Zung Self-Rating Depression Scale (ZSDS). A ZSDS ≥50 was used as the cut-off score for the presence of depressive symptoms. Multivariable logistic regression was used to identify variables associated with depression. RESULTS: The mean estimated glomerular filtration rate (eGFR) in the study sample was 51.59±29.49 ml/min/1.73 m2. The prevalence of depressive symptoms was 37.8% and increased significantly with CKD stage. Being female, a higher level of education, a low income, a larger economic impact of disease cost, comorbid cardiovascular disease, anemia, and impaired physical ability were independently associated with depressive symptoms. CONCLUSION: Our study revealed that depressive symptoms were common among patients with CKD in China. Sociodemographic variables and the clinical characteristics of disease severity were strongly associated with depressive symptoms.

[Expressions of phosphorylated-Smad2 and PTEN in hepatocellular carcinomas and adjacent liver tissues].

OBJECTIVE: To investigate the expressions of phosphorylated Smad2 (P-Smad2) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in hepatocellular carcinoma (HCC) tissues. METHODS: The expressions of P-Smad2 and PTEN were detected using Envision immunohistochemical technique in 31 cases of HCC tissues, 25 cases of HCC adjacent liver tissues and 13 cases of non-hepatocellular carcinoma tissues. RESULTS: The positive expression and staining intensity of PTEN in the cytoplasm of HCC cells (64.5%, 4.19+/-3.31) was significantly lower than those of the cells of the cancer adjacent tissues and non-cancerous tissues (96.0%, 7.88+/-0.93; 100%, 7.77+/-0.93). The staining intensity of PTEN in the cytoplasm of Edmondson pathologic grade III HCC cells was lower than those of the Edmondson grade I. The expression of PTEN was negatively correlated with intrahepatic vascular cancer thrombi (r=-0.43) and the expression of PTEN in the nuclei or cytoplasm of liver cells was negatively correlated with the liver disease progressions (r=-0.34). The positive rate and expression intensity of phosphorylated Smad2 in nuclei of HCC cells were the same as those in cancer adjacent and non-tumor liver tissues. The expression was mostly in the nucleus and cytoplasm of Edmondson grade I HCC cells, cancer adjacent liver tissue cells and non-tumor liver tissues, but its expression was only in the nuclei of Edmondson grade II and III HCC cells. The phosphorylated Smad2 expression appeared in the nuclei and in the cytoplasm of liver cells and it was positively correlated with the severity of the tumor pathology (r=0.22). Spearman correlation analysis revealed a significant inverse correlation between PTEN and phosphorylated Smad2 in HCC tissues (r=-0.73). CONCLUSIONS: The aberrant expressions of PTEN and phosphorylated Smad2 and their interaction may play an important role in the pathogenesis of hepatocellular carcinoma.

Expression of PTEN, PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues.

AIM: To investigate the expressions of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma (HCC) and their significance. METHODS: The expressions of PTEN, PPM1A and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues and 13 non-tumor liver tissues were detected by using Envision immunohistochemical technique. RESULTS: The positive expression (64.52%) and staining intensity (4.19 +/- 3.31) of PTEN in the cytoplasm of HCC were significantly lower and weaker than those in the adjacent or non-tumor liver tissues (97.37%, 7.88 +/- 0.93; 100%, 7.77 +/- 0.93, respectively) (P < 0.05), and its staining intensity in the cytoplasm of HCC, which belongs to Edmondson pathologic grades II-III and above, was also lower than that of grade I and I-II. Furthermore, its location in the nucleus or cytoplasm of liver cells was negatively correlated with the progression of liver disease (r = -0.339, P = 0.002); most of PPM1A might be only expressed in the nucleus of adjacent liver tissues, non-HCC tissues or Edmondson grade I and I-II HCC, but it was mainly expressed in the cytoplasm of HCC with Edmondson grade > or = II, weakly or negatively expressed in the nucleus (P < 0.05), and its location was negatively correlated with the progression of liver disease (r = -0.45, P = 0.0000). P-Smad2, which was mostly located in the nucleus and cytoplasm of grade I and I-II HCC, surrounding or non-tumor liver tissues, was only in the nucleus of HCC with Edmondson grade II and above (P < 0.001), and its location was positively correlated with the disease progression (r = 0.224, P = 0.016). Spearman correlation analysis revealed that P-Smad2 was significantly negatively correlated with PTEN and PPM1A (r = -0.748, P = 0.000; r = -0.366, P = 0.001, respectively); and PTEN and PPM1A were positively correlated with HCC carcinogenesis (r = 0.428, P = 0.000). CONCLUSION: The aberrant location of expression and staining intensity of PTEN, PPM1A and P-Smad2 in HCC and their relationship might have an impact on the pathogenesis of HCC.