Renal interstitial fibrosis is a common outcome of a variety of chronic renal diseases. Here we evaluated the therapeutic efficacy of rhein on renal interstitial fibrosis induced by unilateral ...ureteral obstruction (UUO) and investigated the potential mechanisms. Mice underwent UUO, followed by orally administrated rhein (150 mg/kg/d) or control vehicle. Renal interstitial injury and the degree of fibrosis were evaluated by pathological staining and Western blot. The possible mechanisms were studied by Western blot, indirect immune-fluorescence and enzyme-linked immunosorbent assay. Our results showed that rhein therapy markedly ameliorated renal interstitial fibrotic lesions, reduced α-smooth muscle actin (α-SMA) expression, attenuated deposition of fibronectin (FN). Rhein also suppressed transforming growth factor-β1 (TGF-β1) and its type I receptor expression in obstructed kidneys. In vitro, rhein abolished the α-SMA and fibronectin expression of rat kidney interstitial fibroblasts cells (NRK-49F) induced by TGF-β1. These observations strongly suggest that rhein is a potent inhibitor of renal interstitial fibrosis, and its therapeutic mechanism is, at least in part, blocking interstitial fibroblasts cells activation.
Background: Endoplasmic reticulum (ER) stress-induced podocyte apoptosis plays a critical role in the development of diabetic nephropathy (DN). Here, we tested the hypothesis that suppression of ...PERK-ATF4-CHOP pathway by Astragaloside IV (AS-IV) is associated with inhibition of ER stress-induced podocyte apoptosis in streptozotocin (STZ)-induced diabetic rats. Methods: Diabetic rats were treated with AS-IV at 5 and 10 mg· kg-1· d-1, p.o., for 12 weeks. Albuminuria examination, hematoxylin & eosin staining and TUNEL analysis were performed. Immunohistochemistry, western blot, and real-time PCR were used to detect renal expression of ER chaperone GRP78 and ER-associated apoptosis proteins. Results: Treatment with AS-IV ameliorated albuminuria and renal histopathology in diabetic rats. Diabetic rats had significant increment in podocyte apoptosis as well as phosphorylated PERK and eIF2α in the kidneys, which were attenuated by AS-IV treatment. Furthermore, diabetic rats were found to have increased protein and mRNA expressions of GRP78 and ER-associated apoptosis proteins, such as ATF4, CHOP and TRB3, which were also attenuated by AS-IV treatment. Increased Bax expression and decreased Bcl-2 expression were detected in diabetic rats, and these changes were partially restored by AS-IV treatment. Conclusion: The protective effect of AS-IV on ER stress-induced podocyte apoptosis is associated with inhibition of PERK-ATF4-CHOP pathway. Down-regulation of PERK- ATF4-CHOP pathway by AS-IV may be a novel strategy for the treatment of DN.
Background: Hyperuricemia is an independent risk factor for diabetic kidney disease (DKD) progression. Previous animal and cohort studies have reported that allopurinol administration could be of ...therapeutic benefit in diabetic subjects. However, there has been controversy regarding the effects of allopurinol on DKD. Objectives: The aim of our study was to investigate the efficacy of allopurinol on renal function in patients with DKD by meta-analysis of randomized controlled trials. Method: PubMed, EMBASE, and the Cochrane Library were searched from inception to October 2020. The primary outcome was a change in glomerular filtration rate (GFR). The secondary outcome was the change in albuminuria and serum uric acid (UA). Two reviewers independently assessed for risk of bias and extracted data. Standardized mean difference (SMD) or weighted mean difference (WMD) was calculated with random effects models and was reported with corresponding 95% confidence intervals (CIs). Grading of Recommendations Assessment, Development, and Evaluation (GRADE) of the evidence was performed after meta-analysis. International prospective register of systematic reviews registration CRD42020219132. Results: From 642 potentially relevant citations, 3 studies were ultimately included. Our results showed evident reduction in serum UA after allopurinol intervention (WMD = −103.80, 95% CI −159.05, −48.55, I 2 = 76%; p = 0.04), with a high GRADE of evidence. However, allopurinol did not significantly improve GFR (WMD = 1.07, 95% CI −1.68, 3.82, I 2 = 33%; p = 0.45), with a moderate GRADE of evidence. There was no significant difference on improvement of albuminuria in patients of allopurinol and those in placebo groups (SMD = −0.26, 95% CI −1.03, 0.52, I 2 = 94%; p = 0.52), with a moderate GRADE of evidence. Conclusions: The present research showed that allopurinol did not significantly improve renal function and albuminuria in patients with DKD.
Abstract Most chronic kidney disease inevitably progress to renal fibrosis. Tubular epithelial- to-mesenchymal transition (EMT) is recognized to play major roles in renal fibrosis. Oxymatrine (OM) is ...a major alkaloid component found in a Chinese herb Sophora roots and has many effects. The aim is to investigate the effect of OM on renal tubular EMT and elucidate its mechanism. Mice underwent unilateral ureteral obstruction (UUO) followed by intraperitoneal injection of OM (120 mg/kg) or control vehicle. Human kidney proximal tubular cell line (HK-2) was used and EMT was induced with 5 ng/mL of transforming growth factor-β1 (TGF-β1). In vivo, renal tubulointerstitial fibrosis was induced and E-cadherin was down-regulated, while the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), TGF-β1 and its type I receptor (TGF-βRI) were up-regulated in UUO mice. In contrast, OM significantly ameliorated renal fibrotic lesions and attenuated the expressions of FN, α-SMA, TGF-β1 and TGF-βRI, but increased E-cadherin in the obstructed kidneys. In vitro, OM abolished TGF-β1-mediated E-cadherin suppression and FN, α-SMA and TGF-βRI induction in HK-2 cells in a dose-dependent manner. These observations strongly suggest that the renal protective effects of OM could be mediated by prevention of EMT and manifested as suppression of TGF-β1 and TGF-βRI expressions.
Aims
There is paucity of clinical data comparing continuous infusion (CI) with bolus injection (BI) of intravenous loop diuretics in patients with acute decompensated heart failure (ADHF) and chronic ...renal dysfunction. This study aimed to compare the efficacy and safety of CI versus BI intravenous furosemide administration in patients with ADHF and moderate chronic renal insufficiency.
Methods and results
Acute decompensated heart failure and moderate chronic renal insufficiency with estimated glomerular filtration rate (eGFR) 15.0–44.9 mL/min/1.73 m2 were randomized to start intravenous furosemide by BI or by a 6 h CI. End points included freedom from congestion at 72 h, the degree of dyspnoea assessed using the 0–10 Borg's category ratio scale, net daily urine output, weight loss during the study, length of hospital stay, total urinary sodium excretion, and development of acute kidney injury or electrolyte disturbance. After 72 h of treatment, the rate of the primary endpoint of freedom from congestion in the CI group was significantly higher than that in the BI group (69.05% vs. 43.59%, P = 0.02). The modified Borg scale indicated patients in the CI group had lower dyspnoea score than those in the BI group at 48 h (4.29 ± 1.23 vs. 5.97 ± 1.56; P = 0.02) and 72 h (1.15 ± 0.35 vs. 2.66 ± 0.83; P = 0.003). There were other significant differences favouring the CI group with regard to net urine output at 72 h (5145.98 ± 621.37 mL vs. 3755.95 ± 456.93 mL; P = 0.007), the mean body weight loss (4.72 ± 1.01 kg vs. 3.53 ± 0.73 kg; P = 0.02) and the total urinary sodium excretion (385.05 ± 38.15 vs. 320.33 ± 37.67; P = 0.02). The length of hospitalization in the CI group was significantly shorter than that in the BI group (10.36 ± 4.20 days vs. 15.68 ± 6.15 days; P = 0.02). No significant differences were observed between groups in the frequency of acute kidney injury, tinnitus, electrolyte disturbance or mortality.
Conclusions
Continuous intravenous infusion of furosemide resulted in significantly greater diuresis than bolus administration of an equal dose in patients with moderate chronic renal insufficiency and ADHF, while no differences emerged in terms of side effects or mortality.
Renal interstitial fibrosis is the common end point of progressive renal diseases leading to the deterioration and eventual loss of renal function. This study investigated the effect and potential ...mechanism of cordycepin on activation of renal interstitial fibroblast cells. The time and dose-responses of cordycepin in rat renal interstitial fibroblast (NRK-49F) cells were analyzed. The proliferation of NRK-49F and the expression of α-smooth muscle actin (α-SMA) and fibronectin (FN) were examined. The expression and translocation of Smad proteins also were measured by western blot and indirect immunofluorescence staining. The mRNA level of hepatocyte growth factor (HGF) and the expression of HGF receptor c-Met and its phosphorylation (p-Met) were also detected. Cordycepin suppressed the proliferation of NRK-49F and the expression of α-SMA and FN induced by transforming growth factor-β1 (TGF-β1). The pretreatment of cordycepin markedly attenuated the nuclear translocation and accumulation of activated Smad2/3 in NRK-49F cells. Furthermore, cordycepin not only increased HGF expression, but also induced HGF secretion, as well as HGF receptor phosphorylation in NRK-49F cells. Cordycepin possesses renoprotective activity through suppression myofibroblast activation. This action is mediated, at least in part, by blocking nuclear translocation and accumulation of activated Smad2/3 protein and upregulating anti-fibrotic HGF expression and secretion and HGF receptor activation.
To investigate whether dapagliflozin (as a selective inhibitor of sodium-glucose cotransporter 2), increases the risk of urinary tract infection (UTI) in the treatment of type 2 diabetes mellitus ...(T2DM) remains an ongoing issue. We performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to estimate the short-term and long-term risks of UTI in patients with T2DM who received dapagliflozin at different doses.
The PubMed, EMBASE, and the Cochrane Library and ClinicalTrials.gov website were searched up to December 31, 2022. Only RCTs involving adult T2DM patients with a trial duration of at least 12 weeks were included. The data were summarized using random- or fixed-effects models based on overall heterogeneity. A subgroup analysis was also performed. The review protocol was previously registered in the PROSPERO database (CRD42022299899).
In total, 42 RCTs involving 35,938 patients were assessed for eligibility. The results showed that dapagliflozin imposed a higher risk of UTI compared to placebo and other active treatments, with a heterogeneity of 11% (odds ratio OR 1.17, 95% CI 1.04-1.31, p = 0.006). In the subgroup analysis, dapagliflozin 10 mg/day with a treatment period of > 24 weeks was associated with a significantly higher UTI risk than placebo or other active treatments (OR 1.27, 95% CI 1.13-1.43, p < 0.0001). The ORs for dapagliflozin as monotherapy and combination therapy in the control group were 1.05 (95% CI 0.88-1.25, p = 0.571) and 1.27 (95% CI 1.09-1.48, p = 0.008), respectively.
High-dose, long-term treatment, and add-on therapy of dapagliflozin call for careful consideration of the risk of UTI in T2DM patients.
Podocyte loss and dysfunction play key role during the development of diabetic nephropathy (DN). The aim of this study was to observe the protective effects of astragaloside IV on podocyte in ...diabetic rats and explore its mechanisms preliminary. Healthy male Sprague-Dawley (SD) rats were randomized into normal control group, diabetic nephropathy group and diabetic nephropathy with AS-IV treatment group. DN was induced by intraperitoneal injection of streptozotocin (STZ). AS-IV treatment started 2 weeks before STZ injection and lasted 14 weeks. 24h Urinary proteins were measured 4, 8 and 12 weeks after STZ injection. Body weight, blood glucose, blood urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured 12 weeks after STZ injection. Renal pathology, podocyte morphological changes, podocyte density, protein and mRNA expression of integrin α3, integrin β1 and integrin-linked kinase (ILK) were detected by histopathology, electron microscopy, immunohistochemistry, western blot and real-time PCR, respectively. Hyperglycemia, proteinuria, mesangial expansion and podocyte loss, increased protein expression of ILK and decreased protein expression of integrin α3 and integrin β1 were detected in diabetic rats. AS-IV treatment ameliorated podocyte loss, renal histopathology and podocyte foot process effacement, decreased proteinuria, partially restored protein expression of integrin α3, integrin β1 and ILK. These findings suggested that AS-IV may protect podocyte and ameliorate diabetic nephropathy by inhibiting the expression of ILK and restoring the expression of integrin α3β1 in diabetic rats.
Objective. To explore the role and mechanism of epithelial-mesenchymal transition (EMT) mediated by inflammatory stress-induced TGF-β1 in promoting arteriovenous fistula stenosis. Methods. The ...inflammatory cells HK-2 were cultured by adding TGF-β1. The optimal stimulation time was determined after TGF-β1 was added. HK-2 cells were divided into two groups, DMEM/F12 medium was added to one group (the control group), and the other group was treated with TGF-β1 (10 ng/ml) in serum-free DMEM/F12 medium to stimulate cell differentiation to mesenchymal. Results. TGF-β1 was stably expressed after being transfected into EMT. The expression of TGF-β1 in the experimental group was higher than that in the control group (P<0.05) 7 days after transfection. Western blot showed that TGF-β1 protein expression was higher in the experimental group 7 days after transfection, and no TGF-β1 protein expression was detected in the control group. The smooth muscle cells showed α-SMA expression in the control group, but no cells with expression of SMA and CD31/vWF were found at the same time; α-SMA expression was shown in smooth muscle cells and proliferative myofibroblasts, but no cells with expressions of SMA and CD31/vWF were found at the same time. The observation group showed that the expression of α-SMA was detected in smooth muscle cells and proliferative myofibroblasts, CD31/vWF was also expressed in endothelial cells, and α-SMA and vWF were also observed in endothelial cells, but no CD31 expression was found. Conclusion. The inflammatory stress-induced TGF-β1 could act on epithelial-mesenchymal transition and promote the degree of arteriovenous fistula stenosis
Exploring accurate, noninvasive, and inexpensive disease diagnostic sensors is a critical task in the fields of chemistry, biology, and medicine. The complexity of biological systems and the ...explosive growth of biomarker data have driven machine learning to become a powerful tool for mining and processing big data from disease diagnosis sensors. With the development of bioinformatics and artificial intelligence (AI), machine learning models formed by data mining have been able to guide more sensitive and accurate molecular computing. This review presents an overview of big data collection approaches and fundamental machine learning algorithms and discusses recent advances in machine learning and molecular computational disease diagnostic sensors. More specifically, we highlight existing modular workflows and key opportunities and challenges for machine learning to achieve disease diagnosis through big data mining.
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