Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway.

Diabetic nephropathy (DN), one of the more prevalent microvascular complications in patients diagnosed with diabetes mellitus, is attributed as the main cause of end-stage renal disease (ESRD). Lipotoxicity in podocytes caused by hyperglycemia has been recognised as a significant pathology change, resulting in the deterioration of the glomerular filtration barrier. Research has demonstrated how dapagliflozin, a kind of SGLT2i, exhibits a multifaceted and powerful protective effect in DN, entirely independent of the hypoglycemic effect, with the specific mechanism verified. In this present study, we found that dapagliflozin has the potential to alleviate apoptosis and restore cytoskeleton triggered by high glucose (HG) in vivo and in vitro. We also discovered that dapagliflozin could mitigate podocyte cholesterol accumulation by restoring the expression of ABCA1, which is the key pathway for cholesterol outflows. This research also mechanistically demonstrates that the protective effect of dapagliflozin can be mediated by KLF-5, which is the upstream transcription factor of ABCA1. Taken together, our data suggest that dapagliflozin offers significant potential in alleviating podocyte injury and cholesterol accumulation triggered by high glucose. In terms of the mechanism, we herein reveal that dapagliflozin could accelerate cholesterol efflux by restoring the expression of ABCA1, which is directly regulated by KLF-5.

GDF-15 alleviates diabetic nephropathy via inhibiting NEDD4L-mediated IKK/NF-κB signalling pathways.

Podocyte inflammatory injury has been indicated to play a pivotal role in the occurrence and development of diabetic nephropathy (DN). However, the pathogenesis of inflammation remains unclear. Recent researches have shown that GDF-15, a member of the transforming growth factor-ß superfamily, were elevated under pathological conditions, such as myocardial ischemia, cancer, as well as inflammation. Here, we demonstrated that GDF-15 could alleviate podocyte inflammatory injury by modulating the NF-κB pathway. GDF-15 and other pro-inflammatory factors, such as TNF-α, IL-1ß, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF-15 was also elevated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes. The silence of GDF-15 in HG-stimulated podocytes further augmented inflammation and podocyte injury, while overexpression of GDF-15 significantly reduced the inflammatory response in podocytes. Mechanistically, we demonstrated that GDF-15 could inhibit the nuclear translocation of NF-κB through IKK and IκBα by interaction with ubiquitin ligase NEDD4L. Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.

Inhibition of EZH2 mitigates peritoneal fibrosis and lipid precipitation in peritoneal mesothelial cells mediated by klotho.

BACKGROUND: Peritoneal fibrosis caused by long-term peritoneal dialysis (PD) is the main reason why patients withdraw from PD treatment. Lipid accumulation in the peritoneum was shown to participate in fibrosis, and klotho is a molecule involved in lipid metabolism. GSK343 (enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitor) has been verified to inhibit epithelial mesenchymal transdifferentiation (EMT) and peritoneal fibrosis, but its related mechanism remains unclear. This study aimed to investigate whether lipid accumulation was involved in the effect of GSK343 and its related mechanism. MATERIALS AND METHODS: First, the expression of EZH2, klotho and EMT indices in human peritoneal mesothelial cells (HMrSV5) incubated with high glucose (HG) levels was detected. After EZH2 was inhibited by GSK343, Western blot (WB), wound healing and Transwell assays were used to explore the effect of GSK343. EZH2 and klotho expression was also detected. Oil red O and Nile red staining and triglyceride (TG) detection kits were used to detect lipid accumulation. A rescue experiment with small interfering RNA specific for klotho (si-klotho) on the basis of GSK343 was also conducted to verify that GSK343 exerted its effect via klotho. In in vivo experiments, rats were administered GSK343, and the related index was assessed. RESULTS: In our study, we revealed that the expression of EZH2 was significantly upregulated and klotho was significantly downregulated in HMrSV5 cells induced by high glucose. With the aid of GSK343, we found that lipid deposition caused by HG was significantly decreased. In addition, EMT and fibrosis were also significantly alleviated. Moreover, GSK343 could also restore the downregulation of klotho. To further verify whether klotho mediated the effect of EZH2, a rescue experiment with si-klotho was also conducted. The results showed that si-klotho could counteract the protective effect of GSK343 on high glucose-induced lipid accumulation and fibrosis. In vivo experiments also revealed that GSK343 could relieve peritoneal fibrosis, lipid deposition and EMT by mitigating EZH2 and restoring klotho expression. CONCLUSIONS: Combining these findings, we found that EZH2 regulated lipid deposition, peritoneal fibrosis, and EMT mediated by klotho. To our knowledge, this is the first study to demonstrate the effect of the EZH2-klotho interaction on peritoneal fibrosis. Hence, EZH2 and klotho could act as potential targets for the treatment of peritoneal fibrosis.

Recurrent peritonitis relapse in a patient with atrial septal defect undergoing peritoneal dialysis: a case report.

BACKGROUND: Peritonitis is the most common complication in patients undergoing peritoneal dialysis (PD). Most patients recover with appropriate antibiotic treatment; however, when peritonitis repeatedly relapses, the cause of recurrence must be explored. The relationship between atrial septal defect (ASD), infective endocarditis (IE), and peritonitis is rarely reported. Here, we present a case of recurrent peritonitis due to Staphylococcus aureus in a patient with ASD and IE undergoing PD. CASE PRESENTATION: A 46-year-old woman with chronic renal failure secondary to chronic glomerulonephritis experienced three episodes of peritonitis within 80 days of starting PD. The patient had a history of untreated ASD without symptoms. After undergoing PD for approximately 35 days, the patient was admitted to our hospital on April 5, 2016, due to abdominal pain and fever for 1 week (maximum temperature of 38.5 °C) accompanied by chills and shivering. The PD effluent from the time of her admission was positive for S. aureus. Thereafter, peritonitis recurred each month. When the third episode of peritonitis occurred, transthoracic echocardiography was performed, and a vegetation measuring 9.5 × 6.4 mm attached to the surface of the right ventricle around the ventricular septal membrane was identified. Finally, the patient was diagnosed with IE. Then, ASD repair surgery was successfully performed after the infection was controlled. The patient was followed up for 5 years, with no further episodes of recurrence. CONCLUSIONS: When a patient with ASD undergoing PD develops peritonitis, especially relapsing peritonitis, the possibility of IE is significantly increased. ASD repair surgery may be an important contributing factor to prevent peritonitis recurrence.

Faster lipid ß-oxidation rate by acetyl-CoA carboxylase 2 inhibition alleviates high-glucose-induced insulin resistance via SIRT1/PGC-1α in human podocytes.

Diabetic nephropathy (DN) is becoming a research hotspot in recent years because the prevalence is high and the prognosis is poor. Lipid accumulation in podocytes induced by hyperglycemia has been shown to be a driving mechanism underlying the development of DN. However, the mechanism of lipotoxicity remains unclear. Increasing evidence shows that acetyl-CoA carboxylase 2 (ACC2) plays a crucial role in the metabolism of fatty acid, but its effect in podocyte injury of DN is still unclear. In this study, we investigated whether ACC2 could be a therapeutic target of lipid deposition induced by hyperglycemia in the human podocytes. Our results showed that high glucose (HG) triggered significant lipid deposition with a reduced ß-oxidation rate. It also contributed to the downregulation of phosphorylated ACC2 (p-ACC2), which is an inactive form of ACC2. Knockdown of ACC2 by sh-RNA reduced lipid deposition induced by HG. Additionally, ACC2-shRNA restored the expression of glucose transporter 4 (GLUT4) on the cell surface, which was downregulated in HG and normalized in the insulin signaling pathway. We verified that ACC2-shRNA alleviated cell injury, apoptosis, and restored the cytoskeleton disturbed by HG. Mechanistically, SIRT1/PGC-1α is close related to the insulin metabolism pathway. ACC2-shRNA could restore the expression of SIRT1/PGC-1α, which was downregulated in HG. Rescue experiment revealed that inhibition of SIRT1 by EX-527 counteracted the effect of ACC2-shRNA. Taken together, our data suggest that podocyte injury mediated by HG-induced insulin resistance and lipotoxicity could be alleviated by ACC2 inhibition via SIRT1/PGC-1α.

Associations between the concentrations of CD68, TGF-ß1, renal injury index and prognosis in glomerular diseases.

The present study aimed to investigate the association between the concentrations of CD68, TGF-ß1, renal injury index and prognosis in glomerular diseases. Altogether 218 patients with glomerular diseases admitted to Weifang People's Hospital from January, 2014 to March, 2017 were used as the study group. A total of 100 healthy individuals who visited Weifang People's Hospital for a physical examination during the same time period were used as the control group. The levels of CD68 in peripheral blood obtained from the 2 groups of subjects were detected by flow cytometry, and the expression of TGF-ß1 in serum was detected by enzyme-linked immunosorbent assay (ELISA). The concentrations of CD68 and TGF-ß1 between the 2 groups were compared. The correlation between the concentrations of CD68, TGF-ß1 and renal injury indexes in the study group was analyzed, as well as prognostic significance. The diagnostic value of CD68 and TGF-ß1 in patients with glomerular disease was analyzed using a ROC curve, and the recovery of the patients was observed. The serum concentrations of CD68 and TGF-ß1 in the study group were higher than those in the control group (P<0.05). The concentrations of CD68 and TGF-ß1 in the study group positively correlated with the renal injury indexes, such as blood urea nitrogen (BUN), serum creatinine (SCR), uric acid (UA) and the 24-h urinary protein quantity (P<0.05). ROC curve analysis revealed that the area under the curve of CD68 and TGF-ß1 as regards the diagnostic value in patients with glomerular disease was 0.808 and 0.738, respectively, while the area under the combined detection curve was 0.866. Multivariate unconditional logistic regression analysis revealed that the clinical classification and the concentrations of CD68 and TGF-ß1 were independent prognostic factors in the study group. On the whole, the findings of the present study demonstrate that clinical classification, and the CD68 and TGF-ß1 concentrations are independent prognostic factors for patients with glomerular disease. CD68 and TGF-ß1 have certain value in the diagnosis of glomerular diseases, and may thus be used as predictors of the diagnosis and recovery of glomerular disease.