Renal insufficiency and heart disease are two challenging conditions for the current health-care system. More than 660,000 Americans suffer from end-stage kidney disease (ESKD) and have reached the point of intervention, with 468,000 receiving dialysis therapy. 1 Moreover, in a Duke Electrophysiology Genetic and Genomic Studies (EPGEN) study, estimated glomerular filtration rate (eGFR) decreased by 10 ml/min/1.73 m 2 and mortality increased by 48% (p < 0.001) 2 and major cardiac events account for nearly 50% of deaths in patients with chronic kidney disease (CKD). 3 Renal insufficiency is a common complication of cardiovascular diseases and is a strong independent risk factor for mortality. 4 CKD has been reported in up to 40% of chronic heart failure patients. 5 Moreover, progressive heart failure can lead to renal hypoperfusion and activation of inflammatory factors, and further result in the deterioration of renal function. 5 Similarly, arrhythmia is also a common cause of death in dialysis patients, accounting for 26% and 25% of hemodialysis and peritoneal dialysis deaths respectively. 6 Cardiac resynchronization therapy (CRT) can improve clinical symptoms and left ventricular ejection fraction (LVEF) and reduce

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.