ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling.

Disturbed intrauterine development increases the risk of renal disease. Various studies have reported that Notch signalling plays a significant role in kidney development and kidney diseases. A disintegrin and metalloproteinase domain 10 (ADAM10), an upstream protease of the Notch pathway, is also reportedly involved in renal fibrosis. However, how ADAM10 interacts with the Notch pathway and causes renal fibrosis is not fully understood. In this study, using a prenatal chlorpyrifos (CPF) exposure mouse model, we investigated the role of the ADAM10/Notch axis in kidney development and fibrosis. We found that prenatal CPF-exposure mice presented overexpression of Adam10, Notch1 and Notch2, and led to premature depletion of Six2+ nephron progenitors and ectopic formation of proximal tubules (PTs) in the embryonic kidney. These abnormal phenotypic changes persisted in mature kidneys due to the continuous activation of ADAM10/Notch and showed aggravated renal fibrosis in adults. Finally, both ADAM10 and NOTCH2 expression were positively correlated with the degree of renal interstitial fibrosis in IgA nephropathy patients, and increased ADAM10 expression was negatively correlated with decreased kidney function evaluated by serum creatinine, cystatin C, and estimated glomerular filtration rate. Regression analysis also indicated that ADAM10 expression was an independent risk factor for fibrosis in IgAN. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Whole-Genome Analysis of an Extensive Drug-Resistant Acinetobacter Baumannii ST195 Isolate from a Recipient After DCD Renal Transplantation in China.

BACKGROUND/AIMS: Infection with Acinetobacter baumannii was emerging as one of the leading causes of mortality after donation after cardiac death transpalantion. METHODS: We reported a case of a recipient who underwent DCD renal transplantation and later got infected by A.baumannii. Etests were done to verify the susceptibility test results in clinic. Whole-genome analysis was applied to investigate the resistant mechanism at gene level. RESULTS: The pathogen was isolated from his draining liquid the day after the surgery, and susceptibility test reavealed that it was sensitive to tigecycline. However, the isolate obtained from the draining liquid became tigecycline-resistant after fifteen-day administration of tigecycline. The Susceptibility tests showed that the pathogen recovered from tigecycline resistance and became intermediated to tigecycline. Whole-Genome analysis revealed the genetic level change leading to tigecycline resistance and we identified the location of mutation by comparing the whole genome sequence of the isolates. Three loci were figured out which may contribute to drug resistance, including genes encoding HTH domain protein, MFS transporter and AdeS. CONCLUSION: Understanding the genetic characteristics associated with drug resistance mechanism and antimicrobial profiles of pathogen is important in controlling infection outbreak and preventing serious complications and gives a new insight into the development of antimicrobial agents.

Role of Age-Related Changes in DNA Methylation in the Disproportionate Susceptibility and Worse Outcomes of Sepsis in Older Adults.

Sepsis, a complex multisystem disorder, is among the top causes of hospitalization and mortality in older adults. However, the mechanisms underlying the disproportionate susceptibility to sepsis and worse outcomes in the elderly are not well understood. Recently, changes in DNA methylation have been shown to be linked to aging processes and age-related diseases. Thus, we postulated that age-related changes in DNA methylation may play a role in the onset and prognosis of sepsis in elderly patients. Here, we performed genome-wide methylation profiling of peripheral blood from patients with sepsis and controls. Among the CpG sites whose methylation changes may contribute to an increase in sepsis susceptibility or mortality, 241 sites that possessed age-related changes in DNA methylation in controls may partly explain the increased risk of sepsis in older adults, and 161 sites whose methylation significantly correlated with age in sepsis group may be the potential mechanisms underlying the worse outcomes of elderly septic patients. Finally, an independent cohort was used to validate our findings. Together, our study demonstrates that age-related changes in DNA methylation may explain in part the disproportionate susceptibility and worse outcomes of sepsis in older adults.

Analysis of the dynamic relationship between immune profiles and the clinical features of patients with COVID-19.

BACKGROUND: The novel coronavirus disease (COVID-19) has been declared a global pandemic, with the cumulative number of confirmed cases and deaths exceeding 150 million and 3 million, respectively. Here, we examined the dynamic changes in the immune and clinical features of patients with COVID-19. METHODS: Clinical data of 98 patients with confirmed COVID-19 diagnosis were acquired from electronic medical records and curated. The data were analyzed based on the stage of the admission, deterioration, and convalescence, which included age, sex, severity, disease stages, biochemical indicators, immune cells, inflammatory cytokines, and immunoglobulins. Additionally, temporal changes in the immune response in patients undergoing continuous renal replacement therapy (CRRT) were also examined. RESULTS: Compared to mild stage patients, severe stage patients with COVID-19 exhibited a significant reduction in lymphocyte [23.10 (17.58-33.55) vs. 4.80 (2.95-6.50), P<0.001], monocyte [8.65 (7.28-10.00) vs. 3.45 (2.53-4.58), P<0.001], and NK cell levels [244.00 (150.50-335.00) vs. 59.00 (40.00-101.00), P<0.001] but showed elevated levels of neutrophils [64.90 (56.30-73.70) vs. 90.95 (87.60-93.68), P<0.001], inflammatory cytokines [Interleukin-10, 3.05 (1.37-3.86) vs. 5.94 (3.84-8.35), P=0.001; and tumor necrosis factor-α, 11.50 (6.55-26.45) vs. 12.96 (12.22-36.80), P=0.029], which improved during convalescence. Besides, the number of immune cells-T lymphocytes, B lymphocytes, helper T cells, suppressor T cells, NK cells, and monocytes, except neutrophils-slowly increased in critically ill patients receiving CRRT from 0 to 3 weeks. CONCLUSIONS: Our results indicate that the surveillance of immune cells may contribute to monitoring COVID-19 disease progression, and CRRT is a potential therapeutic strategy to regulate the immune balance in critically ill patients.

Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-κB Pathway.

Organ dysfunction caused by sepsis is life-threatening and results in high mortality. Therapeutic options for sepsis are limited. Pathogenic factors are considered as components of environmental pressure that modify DNA methylation patterns thereby enhancing disease progression. Here, we found that sepsis patients exhibited higher levels of genomic DNA methylation patterns and hypermethylated genes associated with the NF-kB signaling pathway. Therefore, we hypothesized that a DNA methyl transferase inhibitor, Decitabine, may mitigate inflammation and improve survival by inhibiting the NF-κB signaling pathway. To test the hypothesis, mice challenged with caecal ligation and puncture (CLP) were subcutaneously injected with Decitabine solution (0.5, 1, and 1.5 mg/kg) 2 h following operation. Our results indicated that Decitabine reduces DNA methyltransferases (DNMTs), attenuates NF-κB activation, downregulates inflammatory cytokine levels, and inhibits the progression of sepsis. Thus, DNA methylation may be indispensable for sepsis and serve as a predicting factor. The use of Decitabine could represent a novel strategy in the treatment of sepsis.