Serum hydroxycotinine was associated with chronic kidney disease (CKD): a cross-sectional study based on NHANES.

OBJECTIVE: Smoking has been suggested as a modifiable and cardiovascular risk factor for chronic kidney disease (CKD). Although long-term smoking has been associated with CKD, the potential relationship between its metabolite hydroxycotinine and CKD has not been clarified. METHODS: A total of 8,544 participants aged 20 years and above from the National Health and Nutrition Examination Survey (NHANES) 2017 - March 2020 were enrolled in our study. CKD was defined by estimated glomerular filtration rate (eGFR) < 60 mL/(min*1.73 m2). Serum hydroxycotinine was measured by an isotope-dilution high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometric (ID HPLC-APCI MS/MS) method with a lower limit of detections (LLOD) at 0.015 ng/mL. The non-linear relationship was explored with restricted cubic splines (RCS). Pearson's correlation coefficient and a multivariate logistic regression model were used for correlation analysis. RESULTS: Serum hydroxycotinine and eGFR were negatively correlated in both non-CKD group (r= -0.05, p < 0.001) and CKD group (r= -0.04, p < 0.001). After serum hydoxycotinine dichotominzed with LLOD, serum hydroxycotinine ≥ 0.015 ng/mL was negatively correlated with eGFR not only in non-CKD group (r = -0.05, p < 0.001) but also in CKD group (r = -0.09, p < 0.001). After adjusting for comprehensive confounders, results from the multivariate logistic regression analysis showed that participants with serum hydroxycotinine ≥ 0.015 ng/mL had increased odds of CKD (OR = 1.505, p < 0.001). CONCLUSIONS: Serum hydroxycotinine might be positively associated with CKD. Further study is warranted to find the right concentration of hydroxycotinine to measure the CKD.

Oridonin ameliorates renal fibrosis in diabetic nephropathy by inhibiting the Wnt/ß-catenin signaling pathway.

Diabetic nephropathy (DN) is one of the most serious and frequent complications among diabetes patients and presently constitutes vast the cases of end-stage renal disease worldwide. Tubulointerstitial fibrosis is a crucial factor related to the occurrence and progression of DN. Oridonin (Ori) is a diterpenoid derived from rubescens that has diverse pharmacological properties. Our previous study showed that Ori can protect against DN by decreasing the inflammatory response. However, whether Ori can alleviate renal fibrosis in DN remains unknown. Here, we investigated the mechanism through which Ori affects the Wnt/ß-catenin signaling pathway in diabetic rats and human proximal tubular epithelial cells (HK-2) exposed to high glucose (HG) levels. Our results revealed that Ori treatment markedly decreased urinary protein excretion levels, improved renal function and alleviated renal fibrosis in diabetic rats. In vitro, HG treatment increased the migration of HK-2 cells while reducing their viability and proliferation rate, and treatment with Ori reversed these changes. Additionally, the knockdown of ß-catenin arrested cell migration and reduced the expression levels of Wnt/ß-catenin signaling-related molecules (Wnt4, p-GSK3ß and ß-catenin) and fibrosis-related molecules (α-smooth muscle actin, collagen I and fibronectin), and Ori treatment exerted an effect similar to that observed after the knockdown of ß-catenin. Furthermore, the combination of Ori treatment and ß-catenin downregulation exerted more pronounced biological effects than treatment alone. These findings may provide the first line of evidence showing that Ori alleviates fibrosis in DN by inhibiting the Wnt/ß-catenin signaling pathway and thereby reveal a novel therapeutic avenue for treating tubulointerstitial fibrosis.

Activation of AMPK-PGC-1α pathway ameliorates peritoneal dialysis related peritoneal fibrosis in mice by enhancing mitochondrial biogenesis.

BACKGROUND: The pathogenesis of peritoneal dialysis (PD)-related peritoneal fibrosis (PF) is not clearly understood, and current treatment options are limited. METHODS: In this study, the effect of PD-related PF on mitochondrial biogenesis was investigated, and the effect of activation of the adenosine monophosphate-activated protein kinase (AMPK)-PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) pathway on PF was evaluated in mice. RESULTS: In a mouse model of PD-related PF, AMPK-PGC-1α signaling (phospho-AMPK, PGC-1α, NRF-1, NRF-2 and TFAM expression) was downregulated, mitochondrial DNA (mtDNA) levels were reduced, and mitochondrial structure was damaged in the peritoneum. In addition, TdT-mediated dUTP nick-end labeling (TUNEL) staining showed typical apoptosis characteristics in peritoneal mesothelial cells (PMCs). Activation of the AMPK-PGC-1α pathway (PGC-1α overexpression or metformin, which is an agonist of AMPK) upregulated phospho-AMPK, PGC-1α, nuclear respiratory factors 1 (NRF-1) and 2 (NRF-2), and mitochondrial transcription factor A (TFAM) expression and mtDNA content, improved mitochondrial morphological manifestations, inhibited apoptosis of PMCs and alleviated PF. CONCLUSION: Our study may suggest that activation of the AMPK-PGC-1α pathway ameliorates PD-related PF by enhancing mitochondrial biogenesis.

Clinical Features of Maintenance Hemodialysis Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.

BACKGROUND AND OBJECTIVES: Previous reports on the outbreak of coronavirus disease 2019 were on the basis of data from the general population. Our study aimed to investigate the clinical features of patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective, single-center study, we included 49 hospitalized patients on maintenance hemodialysis and 52 hospitalized patients without kidney failure (controls) with confirmed coronavirus disease 2019 at Tongren Hospital of Wuhan University from January 30, 2020 to March 10, 2020. Demographic, clinical, laboratory, and radiologic characteristics and treatment and outcomes data were analyzed. The final date of follow-up was March 19, 2020. RESULTS: The median age of 101 patients was 62 years (interquartile range, 49-72). All patients were local residents of Wuhan. In terms of common symptoms, there were differences between patients on hemodialysis and controls (fatigue [59% versus 83%], dry cough [49% versus 71%], and fever [47% versus 90%]). Lymphocyte counts were decreased (0.8×109/L [patients on hemodialysis] versus 0.9×109/L [controls], P=0.02). Comparing patients on hemodialysis with controls, creatine kinase-muscle and brain type, myoglobin, hypersensitive troponin I, B-type natriuretic peptide, and procalcitonin were increased, and the percentage of abnormalities in bilateral lung was higher in computed tomographic scan (82% versus 69%, P=0.15) and unilateral lung was lower (10% versus 27%, P=0.03). Common complications including shock, acute respiratory distress syndrome, arrhythmia, and acute cardiac injury in patients on hemodialysis were significantly higher. Compared with controls, more patients on hemodialysis received noninvasive ventilation (25% versus 6%, P=0.008). As of March 19, 2020, three patients on hemodialysis (6%) were transferred to the intensive care unit and received invasive ventilation. Seven patients on hemodialysis (14%) had died. CONCLUSIONS: The main symptoms of coronavirus disease 2019 pneumonia, including fever and cough, were less common in patients on hemodialysis. Patients on hemodialysis with coronavirus disease 2019 were at higher risk of death.

The effect of high glucose-based peritoneal dialysis fluids on thioredoxin-interacting protein expression in human peritoneal mesothelial cells.

BACKGROUND: It has been demonstrated that thioredoxin-interacting protein (TXNIP) interacted with NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and participated in the NLRP3 inflammasome activation. Our previous study has demonstrated that in human peritoneal mesothelial cells (HPMCs), exposure to high glucose-based peritoneal dialysis (PD) solutions induced mitochondrial reactive oxygen species (ROS) production, activation of NLRP3 inflammasome and IL-1ß expression. This study aimed to investigate the effect of high glucose-based PD fluids on the TXNIP expression and the underlying mechanisms by which TXNIP-NLRP3 interaction mediates the inflammatory injury to HPMCs in high glucose-based PD fluids conditions. METHODS: TXNIP gene and protein expression was detected by real-time polymerase chain reaction (RT-PCR) and immunoblot. Immunoprecipitation was used to evaluate the interaction between TRX1 and TXNIP, TXNIP and NLRP3. ROS production and IL-1ß expression was examined by flow cytometry and immunoblot and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: It was identified that high glucose-based PD solutions enhance the level of TXNIP gene and protein in cultured HPMCs and a rat-based PD model. We also found that ROS generation induced by high glucose-based PD solutions disrupts the TRX1-TXNIP association, while promoting the binding of TXNIP to NLRP3 in HPMCs. Furthermore, the application of a ROS inhibitor (APDC) to HPMCs blocked the high glucose-based PD solution-induced TXNIP-NLRP3 binding, in addition to ROS production and IL-1ß expression. CONCLUSION: The results of the present study revealed a novel mechanism underlying high glucose-containing PD-mediated peritoneal inflammatory injury, supporting the attenuation of ROS generation as a potential therapeutic strategy to alleviate such pathology.