apelin-13-peptide and Diabetic-Nephropathies

There is no clear information about the level of Apelin-13 in patients with diabetic nephropathy (DN). In this study, we investigated whether there is a relationship between Apelin-13 level and the severity of the disease in patients with DN.. In our case-control study, we included patients who applied to the endocrinology outpatient clinic in 2019. Patients without a history of diabetes were determined as the healthy group (group 1). The patients were divided into 4 groups according to their microalbumin and creatinine levels. Venous blood samples were obtained from all patients for routine laboratory parameters and Apelin-13 levels. Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) for insulin resistance was calculated using the formula: plasma glucose X insulin level/405.. Albumin was found to be significantly lower in group 5 (p = 0.032), hemoglobin A1c, microalbumin/creatinine and HOMA-IR values were found to be significantly lower in group 1 (p < 0.001 for each). Apelin-13 level was found to be significantly higher in group 4 and group 5 (p < 0.001). A negative correlation was found between Apelin-13 and GFR (r = - 0.286, p = 0.003). A positive correlation was found between Apelin-13 and HOMA-IR (r = 0.309, p = 0.009) and microalbumin/creatinine (r = 0.296, p < 0.001).. In patients with DN, Apelin-13 level increases with the severity of the disease and can be used as a biomarker for staging of DN.

Topics: Case-Control Studies; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Insulin Resistance

Diabetes is a serious metabolic disease, and the kidney damage induced by diabetes also seriously affects the survival of patients. Apelin is a molecule that plays a crucial role in lipid metabolism, and recent studies have revealed that apelin‑13, a subtype of apelin, plays an important role in regulating blood glucose levels. However, the role of apelin‑13 in diabetic nephropathy remains unclear. In the present study, a rat model of diabetic nephropathy was constructed by the injection of streptozocin (STZ). During this process, these rats were injected with apelin‑13. The blood glucose, urine protein and insulin levels were determined weekly. Next, the expression of angiotensin domain type 1 receptor‑associated protein (APJ), endothelial nitric oxide synthase (eNOS), E‑cadherin and α‑smooth muscle actin (α‑SMA) in the kidney tissues was determined with western blotting. Then, the endothelial cells of glomerular vessels were cultured with high glucose medium. These cells were treated with apelin‑13 for 24 h. Finally, cell viability of these cells and the expression of APJ, eNOS, E‑cadherin and α‑SMA in these cells were determined with western blotting. As a result, treatment of apelin‑13 induced the lower levels of blood glucose and urine protein. In addition, application of apelin‑13 promoted the production of insulin and alleviated the insulin resistance. Treatment with apelin‑13 promoted the expression of APJ, eNOS and E‑cadherin while it suppressed the expression of α‑SMA in kidney tissues of rats and endothelial cells of glomerular vessels. Furthermore, application of apelin‑13 also promoted the cell viability of these cells. In conclusion, apelin‑13 relieved diabetic nephropathy by promoting the production of nitric oxide (NO) and alleviating the fibrosis of kidney tissues.

Topics: Animals; Antifibrotic Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibrosis; Intercellular Signaling Peptides and Proteins; Kidney; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley

The catabolic enzyme myo-inositol oxygenase (MIOX) is expressed in proximal tubules and up-regulated in the diabetic state. Previously, we reported its transcriptional and translation regulation by high glucose (HG), osmolytes, and fatty acids. However, its epigenetic regulation is unknown. Bisulfite sequencing revealed that both human and mouse MIOX promoters, enriched with CpG sites, are hypomethylated and unmethylated under HG ambience and hyperglycemic states associated with increased MIOX expression. Eletrophoretic mobility shift assays revealed increased binding of unmethylated oligos with nucleoproteins of cells maintained under HG. In addition, a strong binding of specificity protein (Sp)-1 transcription factor with MIOX promoter was observed under HG, especially with unmethylated Sp-1 oligo. Specificity of binding was established by supershift assays and treatment with the Sp-1 inhibitor mithramycin. Promoter analysis revealed an increase in luciferase activity under HG, which was reduced after mutation of the Sp-1-binding site. Sp1 siRNA treatment reduced mRNA and protein expression of Sp-1 and MIOX and generation of reactive oxygen species derived from NADPH oxidase (NOX)-4 and mitochondrial sources. In addition, there was reduced expression of hypoxia-inducible factor-1α relevant in the pathogenesis of diabetic nephropathy. Sp1 siRNA treatment reduced fibronectin expression, an extracellular matrix protein that is increased in diabetic nephropathy and tubulopathy. HG-induced MIOX expression was also reduced with the treatment of apelin-13, which deacetylates histones. Overall, these findings highlight the epigenetic regulation of MIOX in the pathogenesis of diabetic tubulopathy.

Topics: Animals; Base Sequence; Binding Sites; Cell Line; CpG Islands; Diabetic Nephropathies; DNA Methylation; Fibronectins; Gene Deletion; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inositol Oxygenase; Intercellular Signaling Peptides and Proteins; Kidney Tubules; Mice, Inbred C57BL; Mitochondria; Nucleoproteins; Oxidation-Reduction; Promoter Regions, Genetic; Protein Binding; RNA, Small Interfering; Sp1 Transcription Factor

Diabetic nephropathy is the primary cause of end-stage renal disease. Increasing numbers of patients are suffering from this disease and therefore novel medications and therapeutic approaches are urgently needed. Here, we investigated whether apelin-13, the most active member of the adipokine apelin group, could effectively suppress the development of nephropathy in Akita mouse, a spontaneous type 1 diabetic model. Apelin-13 treatment decreased diabetes-induced glomerular filtration rate, proteinuria, glomerular hypertrophy, mesangial expansion and renal inflammation. The inflammatory factors, activation of NF-κB, histone acetylation and the enzymes involved in histone acetylation were further examined in diabetic kidneys and high glucose- or sodium butyrate-treated mesangial cells in the presence or absence of apelin-13. Apelin-13 treatment inhibited diabetes-, high glucose- and NaB-induced elevation of inflammatory factors, and histone hyperacetylation by upregulation of histone deacetylase 1. Furthermore, overexpression of apelin in mesangial cells induced histone deacetylation under high glucose condition. Thus, apelin-13 may be a novel therapeutic candidate for treatment of diabetic nephropathy via regulation of histone acetylation.

Topics: Acetylation; Animals; Diabetic Nephropathies; Glomerular Filtration Rate; Histones; Intercellular Signaling Peptides and Proteins; Mice; NF-kappa B; Protein Processing, Post-Translational

Topics: Animals; Diabetic Nephropathies; Histones; Intercellular Signaling Peptides and Proteins; Protein Processing, Post-Translational