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Background/Aims Diabetic nephropathy (DN) is one of the main causes of end-stage kidney disease worldwide. Emerging studies have suggested that its pathogenesis is distinct from nondiabetic renal diseases in many aspects. However, it still lacks a comprehensive understanding of the unique molecular mechanism of DN. Methods A total of 255 Affymetrix U133 microarray datasets (Affymetrix, Santa Calra, CA, USA) of human glomerular and tubulointerstitial tissues were collected. The 22 215 Affymetrix identifiers shared by the Human Genome U133 Plus 2.0 and U133A Array were extracted to facilitate dataset pooling. Next, a linear model was constructed and the empirical Bayes method was used to select the differentially expressed genes (DEGs) of each kidney disease. Based on these DEG sets, the unique DEGs of DN were identified and further analyzed using gene ontology and pathway enrichment analysis. Finally, the protein–protein interaction networks (PINs) were constructed and hub genes were selected to further refine the results. Results A total of 129 and 1251 unique DEGs were identified in the diabetic glomerulus (upregulated n = 83 and downregulated n = 203) and the diabetic tubulointerstitium (upregulated n = 399 and downregulated n = 874), respectively. Enrichment analysis revealed that the DEGs in the diabetic glomerulus were significantly associated with the extracellular matrix, cell growth, regulation of blood coagulation, cholesterol homeostasis, intrinsic apoptotic signaling pathway and renal filtration cell differentiation. In the diabetic tubulointerstitium, the significantly enriched biological processes and pathways included metabolism, the advanced glycation end products–receptor for advanced glycation end products signaling pathway in diabetic complications, the epidermal growth factor receptor (EGFR) signaling pathway, the FoxO signaling pathway, autophagy and ferroptosis. By constructing PINs, several nodes, such as AGR2, CSNK2A1, EGFR and HSPD1, were identified as hub genes, which might play key roles in regulating the development of DN. Conclusions Our study not only reveals the unique molecular mechanism of DN but also provides a valuable resource for biomarker and therapeutic target discovery. Some of our findings are promising and should be explored in future work.

A humanized anti-Toll-like receptor 4 (TLR4) monoclonal antibody (mAb) was previously produced using phage antibody library technology, and it was found that the mAb could effectively ameliorate lipopolysaccharide (LPS)-induced damage in macrophages. The present study investigated the protective effects exerted by the humanized anti-TLR4 mAb against LPS-induced acute kidney injury (AKI), as well as the underlying mechanisms. Female C57BL/6 mice were randomly divided into four groups (n=8 per group): i) Control; ii) LPS; iii) LPS + humanized anti-TLR4 mAb (1 µg/g); and iv) LPS + humanized anti-TLR4 mAb (10 µg/g). Serum creatinine, blood urea nitrogen, IL-6, TNFα and IL-1β levels were then examined, followed by renal pathology assessment, immunohistochemical staining, reverse transcription-quantitative PCR and western blotting to assess apoptosis/survival/inflammation-related molecules and kidney injury molecule (KIM)-1. The humanized anti-TLR4 mAb successfully ameliorated LPS-induced AKI and renal pathological damage. The humanized anti-TLR4 mAb also dose-dependently suppressed LPS-induced elevations in serum IL-6, TNFα and IL-1β, and decreased the renal expression levels of myeloid differentiation primary response 88 (MyD88), IKKα/β, IκB, p65 and KIM-1. Compared with the LPS group, renal Bax and KIM-1 expression levels were significantly downregulated, and Bcl-2 expression was notably upregulated by the humanized anti-TLR4 mAb. Moreover, the humanized anti-TLR4 mAb also significantly decreased the protein expression levels of MyD88, phosphorylated (p)-IKKα/β, p-IκB and p-p65 in the renal tissues compared with the LPS group. Therefore, the present study indicated that the anti-inflammatory effects of the humanized anti-TLR4 mAb against LPS-related AKI in mice were mediated via inhibition of the TLR4/NF-κB signaling pathway.

Cardiac resynchronization therapy with or without a defibrillator (CRT(D)) and implantable cardioverter defibrillator (ICD) may reduce the risk of arrhythmia or heart failure-specific mortality and improves the prognosis of patients with chronic kidney disease (CKD) or dialysis. The aim of this study was to perform a meta-analysis investigating the relationship between CRT(D)/ICD and renal insufficiency. Cochrane Library, Web of Science, Embase, and Pubmed were systematically searched from inception to 29 October 2019. We included studies that report all-cause mortality of patients with renal insufficiency who received CRT(D)/ICD therapy. Twenty-six studies (n = 119,263) were included, exploring the relationship between CRT(D)/ICD and renal insufficiency from two aspects: (1) Compared with ICD-only, CRT(D) was associated with lower risk of all-cause mortality in CKD patients (odds ratios (OR) = 0.67; 95% confidence interval (CI), 0.60 to 0.75). For non-primary prevention (secondary prevention or both), the analysis revealed a lower risk of all-cause mortality in the ICD group than in the no-ICD group (OR = 0.47; 95% CI, 0.40 to 0.55). (2) CKD increased all-cause mortality in comparison with control group (OR = 2.12; 95% CI, 1.85 to 2.44), and so did dialysis (OR = 2.53; 95% CI, 2.34 to 2.73). Furthermore, compared with CKD3 (eGFR: 30-59 ml/min/1.73 m2 ), CKD4/5 (eGFR

Background. M-type phospholipase A2 receptor (PLA2R) is the first autoantigen responsible for idiopathic membranous nephropathy (IMN). However, serum PLA2R antibody (PLA2R-Ab) can be inaccurate in distinguishing between IMN and secondary membranous nephropathy, while renal PLA2R antigen (PLA2R-Ag) emerges as an ancillary diagnostic. The present study is aimed at examining the associations between PLA2R-Ab in sera and PLA2R-Ag in kidneys in IMN patients. Methods. A total of 93 patients with IMN were retrospectively identified. Their serum PLA2R-Ab and renal PLA2R-Ag expression levels were determined, and the clinical correlations between these parameters and clinical features were examined. Results. The sensitivities of serum PLA2R-Ab and renal PLA2R-Ag for diagnosing IMN were 74.2% and 88.2%, respectively (P<0.001), with poor consistency. Higher serum PLA2R-Ab levels were correlated to stronger renal PLA2R-Ag expression (P=0.048). Patients with positive PLA2R-Ab significantly differed from those with negative levels, in terms of proteinuric levels over 24 hours (4.54 vs. 3.46 g/day, P=0.015) and serum albumin (23.28 vs. 27.95 g/L, P=0.038). Among patients with positive renal PLA2R-Ag, patients with positive PLA2R-Ab had significantly higher 24-hour proteinuria, when compared to patients with negative PLA2R-Ab (4.57 vs. 3.08 g/day, P=0.005). Among those with positive PLA2R-Ab in sera, their PLA2R-Ab levels were correlated with the estimated glomerular filtration and serum creatinine. Conclusion. Serum PLA2R-Ab exhibits a closer correlation with proteinuric severity and renal function, when compared to renal PLA2R-Ag.

Cytochrome c release and mitochondrial permeability transition (MPT) play important roles in apoptosis. In this study, we found that selenium, an essential trace element, induced mitochondrial membrane potential (Delta psi(m)) loss, swelling, and cytochrome c release in isolated mitochondria. All of the above observations were blocked by cyclosporin A (CsA), which is a specific inhibitor to permeability transition pore (PTP), indicating selenite-induced mitochondrial changes were mediated through the opening of PTP. In physiological concentration, selenite could induce mitochondria at low-conductance PTP 'open' probability, which is correlated to regulate the physiological function, whereas in toxic concentration, induce mitochondria at high-conductance PTP 'open' probability and rapidly undergo a process of osmotic swelling following diffusion toward matrix as for inducer (Ca(2+)/P(i)). Selenite also induced other mitochondrial marker enzymes including monoamine oxidase (MAO) and mitochondria aspartate aminotransferase (mAST). Oligomycin inhibited the selenite-induced cytochrome c release and Delta psi(m) loss, showing that F(0)F(1)-ATPase was important in selenite or Ca(2+)/P(i)-induced MPT.

In this study, high-resolution 600-MHz 1H-NMR (nuclear magnetic resonance) spectroscopies were used to compare the urinary metabolic profiles of healthy humans and humans in a high-selenium area of China. NMR biomarkers for renal and liver lesions were observed by comparing the urine 1H-NMR spectra. In urinary excretion, the concentrations in human urine samples of formate, lactate, acetate, hippurate, and alanine in overexposure to selenium were increased, whereas citrate, creatine, and TMAO excretion were decreased compared with that of the healthy human--some of them even disappeared. An interesting result was the appearance of formate in urine, which has previously been shown to lead to acidosis and chronic renal failure and interfere with the lumen and proximal tubular cells. The level of creatine was associated with the seminal activity. The changes of acetate and citrate may explain the disorder of the cellular energy metabolism caused by selenium, and the changes of other amino acids were a result of the reuptake of these compounds that had been blocked in the glomerulus and proximal tubule. The results elucidate the renal/liver lesion in humans in high-selenium area by 1H-NMR spectroscopy and offer the molecular basic of selenium toxicity.

Selenium (Se) is an essential trace element in animals and human, however, excess Se intake can result in adverse health effects. Se supplementation increased glutathione peroxidase (GSH-Px) and thioredoxin reductase (TR) expressions in Se-deficient rats. However, little information is available on the relationship between Se overexposure on GSH-Px and TR mRNA levels and activities. In this study, the effects of Se overexposure on GSH-Px and TR mRNA levels and activities were investigated by reverse transcription-polymerase chain reaction (RT-PCR) and activity assay. Experimental groups of male Wistar rats were injected intraperitoneally (i.p.) with sodium selenite at doses of 20, 40, and 80 microg Se/kg/d for 15 d, respectively. Se levels were elevated dose-dependently in rat liver, kidney, and testis tissues. GSH-Px mRNA levels and activities in the liver and testis for rats injected with 20 microg Se/kg/d were increased significantly as compared with those in the control group. However, intraperitoneal injection of 40 and 80 microg Se/kg/d dramatically decreased GSH-Px mRNA expression and activity in liver and testis. The changes of TR mRNA level and activity in the liver and kidney were similar to those of GSH-Px in the liver and testis when supplemented with 40 and 80 microg Se/kg/d. There were no significant effects of Se status on kidney GSH-Px and testis TR expressions. The results suggested that Se overexposure had an adverse effect on GSH-Px and TR mRNA levels and activities, and there could be tissue differences in the regulation of selenoprotein levels.

Transmucosal delivery is a suitable route for insulin non-injection administration. In this study, the hypoglycaemic effect of INSULIN BUCCAL SPRAY (IBS), a formulation with soybean lecithin and propanediol combined as absorption enhancer for insulin on diabetic rabbits and rats, were investigated. The hypoglycaemic rate was calculated and the pharmacodynamics and pharmacokinetics of the formulation in rabbits were studied. The results show that when the diabetic rabbits were administrated with IBS in dosages of 0.5, 1.5 and 4.5 U kg −1 , the blood glucose level decreased significantly compared with that of the control group and the hypoglycaemic effect lasted over 5 h. The blood glucose decreasing rates are 22.4, 48.1 and 53.5%, respectively. The average bioavailability of IBS by buccal delivery versus subcutaneous injection is 29.2%. Meanwhile, the diabetic rats were administrated with IBS in dosages of 1.0, 3.0 and 9.0 U kg −1 , the blood glucose level decreased significantly compared with that of the control group and the hypoglycaemic effect lasted over 4 h. The blood glucose decreasing rates are 24.6, 47.5 and 59.6%, respectively. Furthermore, the penetration of fluorescein isothiocyanate (FITC)-labelled insulin through rabbit buccal mucosa was investigated by scanning the distribution of the fluorescent probe in the epithelium using confocal laser scanning microscopy. The results revealed that FITC–insulin can pass through the buccal mucosa promoted by the enhancer and the passage of insulin across the epithelium includes both intracellular and paracellular routes. From the rabbit and rat experimental results showed that IBS is an effective buccal delivery system, which is promising for clinical trial and the future clinical application.