Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney diseaseResearch in context

Background: Acute kidney injury (AKI) may lead to the development of chronic kidney disease (CKD), i.e. AKI-CKD transition, but the underlying mechanism remains largely unclear. Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded or misfolded proteins in ER resulting in a cellular stress response. The role of ER stress in AKI-CKD transition remains unknown. Methods: In this study, we examined ER stress in the mouse model of AKI-CKD transition after unilateral renal ischemia-reperfusion injury (uIR). To determine the role of ER stress in AKI-CKD transition, we tested the effects of two chemical chaperones: Tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). Findings: uIR led to the induction of ER stress in kidneys, as indicated by increased expression of UPR molecules CHOP (C/EBP homologous protein) and BiP(binding immunoglobulin protein; also called GRP78–78 kDa glucose­regulated protein). Given at 3 days after uIR, both TUDCA and 4-PBA blocked ER stress in post-ischemic kidneys. Notably, both chemicals promoted renal recovery and suppressed tubulointerstitial injury as manifested by the reduction of tubular atrophy, renal fibrosis and myofibroblast activation. Inhibition of ER stress further attenuated renal tubular epithelial cell apoptosis, inflammation and autophagy in post-ischemic kidneys. Interpretation: These findings suggest that ER stress contributes critically to the development of chronic kidney pathologies and CKD following AKI, and inhibition of ER stress may represent a potential therapeutic strategy to impede AKI-CKD transition. Keywords: ER stress, AKI-CKD transition, Renal ischemia-reperfusion, Fibrosis, Apoptosis, Autophag

Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension

Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair

Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions. Hypoxia-inducible factors (HIFs) are the “master” transcription factors responsible for gene expression in hypoxia. Recent researches demonstrate that HIFs play an important role in kidney injury and repair by regulating HIF target genes, including microRNAs. However, there are controversies regarding the pathological roles of HIFs in kidney injury and repair. In this review, we describe the regulation, expression, and functions of HIFs, and their target genes and related functions. We also discuss the involvement of HIFs in AKI and kidney repair, presenting HIFs as effective therapeutic targets

Correlation between the Effects of Acupuncture at Taichong

Functional magnetic resonance imaging (fMRI) has been shown to detect the specificity of acupuncture points, as proved by numerous studies. In this study, resting-state fMRI was used to observe brain areas activated by acupuncture at the Taichong (LR3) acupoint. A total of 15 healthy subjects received brain resting-state fMRI before acupuncture and after sham and true acupuncture, respectively, at LR3. Image data processing was performed using Data Processing Assistant for Resting-State fMRI and REST software. The combination of amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) was used to analyze the changes in brain function during sham and true acupuncture. Acupuncture at LR3 can specifically activate or deactivate brain areas related to vision, movement, sensation, emotion, and analgesia. The specific alterations in the anterior cingulate gyrus, thalamus, and cerebellar posterior lobe have a crucial effect and provide a valuable reference. Sham acupuncture has a certain effect on psychological processes and does not affect brain areas related to function

A prognostic score for patients with acute-on-chronic liver failure treated with plasma exchange-centered artificial liver support system

Abstract Artificial liver support system (ALSS) therapy is widely used in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). We aimed to develop a predictive score to identify the subgroups who may benefit from plasma exchange (PE)-centered ALSS therapy. A total of 601 patients were retrospectively enrolled and randomly divided into a derivation cohort of 303 patients and a validation cohort of 298 patients for logistic regression analysis, respectively. Five baseline variables, including liver cirrhosis, total bilirubin, international normalized ratio of prothrombin time, infection and hepatic encephalopathy, were found independently associated with 3-month mortality. A predictive PALS model and the simplified PALS score were developed. The predicative value of PALS score (AUROC = 0.818) to 3-month prognosis was as capable as PALS model (AUROC = 0.839), R score (AUROC = 0.824) and Yue-Meng’ score (AUROC = 0.810) (all p > 0.05), and superior to CART model (AUROC = 0.760) and MELD score (AUROC = 0.765) (all p  90% for 3-month mortality, while PALS score of 6–9 had both specificity and positive predictive value of > 90%. Patients with PALS score of 3–5 who received 3–5 sessions of ALSS therapy had much lower 3-month mortality than those who received 1–2 sessions (32.8% vs. 59.2%, p < 0.05). The more severe patients with PALS score of 6–9 could still benefit from ≥ 6 sessions of ALSS therapy compared to ≤ 2 sessions (63.6% vs. 97.0%, p < 0.05). The PALS score could predict prognosis reliably and conveniently. It could identify the subgroups who could benefit from PE-centered ALSS therapy, and suggest the reasonable sessions. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032055. Registered 19th April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52471

The negative feedback loop of NF-κB/miR-376b/NFKBIZ in septic acute kidney injury

Sepsis is the leading cause of acute kidney injury (AKI). However, the pathogenesis of septic AKI remains largely unclear. Here, we demonstrate a significant decrease of microRNA-376b (miR-376b) in renal tubular cells in mice with septic AKI. Urinary miR-376b in these mice was also dramatically decreased. Patients with sepsis with AKI also had significantly lower urinary miR-376b than patients with sepsis without AKI, supporting its diagnostic value for septic AKI. LPS treatment of renal tubular cells led to the activation of NF-κB, and inhibition of NF-κB prevented a decrease of miR-376b. ChIP assay further verified NF-κB binding to the miR-376b gene promoter upon LPS treatment. Functionally, miR-376b mimics exaggerated tubular cell death, kidney injury, and intrarenal production of inflammatory cytokines, while inhibiting miR-376b afforded protective effects in septic mice. Interestingly, miR-376b suppressed the expression of NF-κB inhibitor ζ (NFKBIZ) in both in vitro and in vivo models of septic AKI. Luciferase microRNA target reporter assay further verified NFKBIZ as a direct target of miR-376b. Collectively, these results illustrate the NF-κB/miR-376b/NFKBIZ negative feedback loop that regulates intrarenal inflammation and tubular damage in septic AKI. Moreover, urinary miR-376b is a potential biomarker for the diagnosis of AKI in patients with sepsis