ABSTRACT
AIMS/INTRODUCTION: This study investigated the roles of voltage-dependent anion channel 1-related differentially expressed genes (VRDEGs) in diabetic nephropathy (DN). MATERIALS AND METHODS: We downloaded two datasets from patients with DN, namely, GSE30122 and GSE30529, from the Gene Expression Omnibus database. VRDEGs associated with DN were obtained from the intersection of voltage-dependent anion channel 1-related genes from the GeneCards database, and differentially expressed genes were screened according to group (DN/healthy) in the two datasets. The enriched pathways of the VRDEGs were analyzed. Hub genes were selected using a protein-protein interaction network, and their predictive value was verified through receiver operating characteristic curve analysis. The CIBERSORTx software examined hub genes and immune cell infiltration associations. The protein expression of hub genes was verified through immunohistochemistry in 16-week-old db/db mice for experimentation as a model of type 2 DN. Finally, potential drugs targeting hub genes that inhibit DN development were identified. RESULTS: A total of 57 VRDEGs were identified. The two datasets showed high expression of the PI3K, Notch, transforming growth factor-ß, interleukin-10 and interleukin-17 pathways in DN. Five hub genes (ITGAM, B2M, LYZ, C3 and CASP1) associated with DN were identified and verified. Immunohistochemistry showed that the five hub genes were highly expressed in db/db mice, compared with db/m mice. The infiltration of immune cells was significantly correlated with the five hub genes. CONCLUSIONS: Five hub genes were significantly correlated with immune cell infiltration and might be crucial to DN development. This study provides insight into the mechanisms involved in the pathogenesis of DN.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Animals , Humans , Mice , Caspase 1 , Databases, Factual , Diabetic Nephropathies/genetics , Health Status , Voltage-Dependent Anion Channel 1ABSTRACT
BACKGROUND: The aim of this study was to explore the mechanism of complement C3a mediating podocyte injury during ischemia-reperfusion acute kidney injury (IR-AKI) and post-injury fibrosis. METHODS: Renal artery clamping was used to establish IR-AKI and post-injury fibrosis model. HE and Masson staining were performed to observe renal fibrosis. The protein abundance levels were measured along with inflammatory markers, renal complement C3. Podocytes were treated with C3a with or without Toll-like receptor 4(TLR4) inhibitor. The effects of TLR4 up-regulation by TLR4 plasmids were examined. RESULTS: C3-/- resulted in amelioration of renal dysfunction by reducing podocyte damage and renal fibrosis. Immunoblot with renal tissue homogenates from IR-AKI mice revealed that C3-/- decreased TLR4/Nuclear Factor-κB (NFκB)-P65. CONCLUSION: Our results indicate that modulating C3/TLR4/NFκB-P65 signaling pathway is a novel therapeutic target for the IR-AKI and post-injury fibrosis.
Subject(s)
Acute Kidney Injury , Podocytes , Reperfusion Injury , Mice , Animals , Podocytes/metabolism , Podocytes/pathology , Complement C3/genetics , Complement C3/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/therapeutic use , Kidney/pathology , Acute Kidney Injury/genetics , Acute Kidney Injury/metabolism , Signal Transduction , NF-kappa B/genetics , NF-kappa B/metabolism , Reperfusion Injury/drug therapy , Ischemia/metabolism , Ischemia/pathology , Reperfusion , FibrosisABSTRACT
Introduction: With the invention and improvement of the carbon monoxide (CO) breath test, the role of shortened red blood cell life span (RBCLS) in renal anemia, an independent risk factor for cardiovascular events in patients with chronic kidney disease (CKD), is gradually attracting attention. Considering that heart failure is the leading cause of morbidity and mortality in patients with CKD, this study investigated the correlation between the RBCLS and the cardiac structure and function in non-dialysis patients with CKD stages 3−5, aiming to provide new ideas to improve the long-term prognosis of CKD patients. Methods: One hundred thirty-three non-dialysis patients with CKD stages 3−5 were tested for RBCLS. We compared the serological data, cardiac ultrasound results, and follow-up prognosis of patients with different RBCLS. Results: As the RBCLS shortened, the patients' blood pressure, BNP, and CRP gradually increased, most significantly in patients with an RBCLS < 50 d. Patients with an RBCLS < 50 d had substantially lower hemoglobin (Hb), hematocrit, and albumin levels than those with an RBCLS ≥ 50 d. The cardiac ultrasound results show that patients with an RBCLS < 50 d had significantly larger atrial diameters than those with an RBCLS ≥ 50 d and were associated with more severe diastolic dysfunction. Patients with an RBCLS < 50 d had a 3.06 times greater risk of combined heart failure at baseline than those with an RBCLS ≥ 70 d and a higher risk of heart failure at follow-up. CKD stage 5 patients with an RBCLS < 50 d were more likely to develop heart failure and require renal replacement therapy earlier than patients with an RBCLS ≥ 50 d. Conclusions: In non-dialysis patients with CKD stages 3−5, there is a correlation between the red blood cell life span and cardiac structure and function. The RBCLS may also impact the renal prognosis of CKD patients.
