Aspirin attenuates podocyte injury in diabetic rats through overriding cyclooxygenase-2-mediated dysregulation of LDL receptor pathway.

AIM: This study aimed to investigate the effects of aspirin on podocyte injury and its underlying mechanisms in diabetic nephropathy (DN). METHODS: Eight-week-old male Sprague-Dawley rats were divided into three groups: non-diabetic rats (Control), streptozotocin-induced diabetic rats (DM), and diabetic rats treated with aspirin (DM + Aspirin) for 12 weeks. Intracellular lipid accumulation was evaluated by Oil Red O staining and quantitative free cholesterol assays. Podocyte injury and the levels of COX-2, inflammatory cytokines, and low-density lipoprotein receptor (LDLr) pathway-related proteins were evaluated by electron microscopy, immunohistochemical staining, and Western blotting, respectively. RESULTS: Lipid levels and urinary albumin-creatinine ratios were higher in the DM rats than in the Control rats. Periodic acid-Schiff staining showed glomerular hypertrophy and mild mesangial area widening in the DM rats. Electron microscopy showed that the podocyte foot processes were significantly flattened or absent in the DM rats. The protein expression levels of WT-1 and nephrin in the podocytes of DM rats were reduced. Interestingly, lipid accumulation in the kidneys of DM rats was significantly increased due to increased protein expression levels of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-2, cyclooxygenase-2 (COX-2), and inflammatory cytokines. Confocal immunofluorescent staining showed that COX-2 and WT-1 were co-expressed. Furthermore, COX-2 protein expression levels were positively correlated with LDLr protein expression levels. However, when COX-2 expression was inhibited by aspirin, these changes in the DM rats were significantly attenuated. CONCLUSION: Aspirin attenuates podocyte injury in DN, which may be through COX-2-mediated dysregulation of LDLr pathway.

Lipoprotein(a) accelerated the progression of atherosclerosis in patients with end-stage renal disease.

BACKGROUND: Increased plasma level of lipoprotein(a) (Lpa) is a risk factor of cardiovascular diseases. This study aimed to explore the role of Lpa in the progression of atherosclerosis in patients with end-stage renal disease (ESRD) and to investigate whether its potential mechanism is mediated by CXC chemokine ligand 16 (CXCL16) and low-density lipoprotein receptor (LDLr). METHODS: This is a retrospective clinical study. From January 2015 to April 2016, forty-six ESRD patients from Danyang First People's Hospital were investigated. The patients were grouped according to their plasma Lpa levels: control group (Lpa < 300 mg/l, n = 23) and high Lpa group (Lpa ≥ 300 mg/l, n = 23). ESRD Patients with acute infective diseases, cancer, and/or chronic active hepatitis were excluded. Biochemical indexes and lipid profiles of the patients were measured. Surgically removed tissues from the radial arteries of ESRD patients receiving arteriovenostomy were used for the preliminary evaluation of atherosclerosis. Haematoxylin-eosin (HE) and filipin staining were used to observe foam cell formation. Protein expression levels of Lpa, CXCL16, and LDLr were detected by immunohistochemistry staining and immunofluorescent staining. RESULTS: There was more foam cell formation and cholesterol accumulation in the radial arteries of the high Lpa group than in those of the control group. Furthermore, the expression levels of Lpa, CXCL16, and LDLr were significantly increased in the radial arteries of the high Lpa group. Correlation analyses showed that the protein expression levels of Lpa (r = 0.72, P < 0.01), LDLr (r = 0.54, P < 0.01), and CXCL16 (r = 0.6, P < 0.01) in the radial arteries of ESRD patients were positively correlated with the plasma Lpa levels. Further analyses showed that the co-expression of Lpa with LDLr or CXCL16 was increased in the high Lpa group. CONCLUSIONS: High plasma Lpa levels accelerated the progression of atherosclerosis in ESRD through inducing Lpa accumulation in the arteries, which was associated with LDLr and CXCL16. These two lipoproteins could both be major lipoprotein components that regulate the entry of Lpa into arterial cells.

Apo E gene polymorphism affects development of type 2 diabetic nephropathy in Asian populations, especially in East Asians: an updated meta-analysis.

BACKGROUND: Many studies have determined the correlation between the Apolipoprotein E (APO E) gene polymorphisms and diabetic nephropathy, but their results are inconclusive. MATERIAL/METHODS: With the aim to confirm this correlation, we performed a meta-analysis of 16 studies. The dichotomous data are presented as the odds ratio (OR) with a 95% confidence interval (CI). RESULTS: The results of our study indicate that APO ε2 allele among the pooled Asian populations were more likely to show high risk of DN development (2 allele vs. ε3 allele: pooled OR =1.629, 95% CI=1.010-2.628, P=0.045). For further analysis, the APO e2 allele was associated with progress of DN in the group with duration >10 years, but not in the group with duration <10 years (ε2 allele vs. ε3 allele: pooled OR=1.920, 95% CI=1.338-2.754, P<0.001). The APO e2 polymorphism increased the susceptibility to DN in Asian population compared with healthy people (ε2 allele vs. ε3 allele: pooled OR=1.629, 95% CI=1.010-2.628, P=0.045). CONCLUSIONS: Development of DN is associated with APO E polymorphisms in Asian populations, especially in East Asians.