FOSL2 Aggravates Renal Injury in Diabetic Nephropathy by Activating NF-κB Signaling Pathway

Abstract

Background: Diabetic nephropathy (DN) is one of the complications of diabetes, and may lead to abnormal renal functions. Although many studies confirmed that proteins serve as essential factors in DN progression, the function of Fos-like antigen 2 (FOSL2) in DN has not been properly investigated. The purpose of this study is to explore the regulatory role of FOSL2 in DN progression. Methods: The rats were divided into four groups such as Sham, DN, DN+Adeno-associated virus (AAV)-Scramble, and DN+AAV-shFOSL2 groups. The cells were divided into the control, high glucose (HG), HG+negative control (si-NC), and HG+si-FOSL2 groups. The levels of fasting blood glucose (FBG) and oral glucose tolerance (OGTT) were measured through the glucometer. The levels of glycosylated hemoglobin (HbA1c), serum creatinine (Scr), and blood urea nitrogen (BUN) were measured through the automatic biochemistry analyzer. The damage of renal tissues was evaluated through hematoxylin-eosin (HE) staining. The cell apoptosis was measured through TdT-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry. The mRNA expression was examined through Real-time quantitative polymerase chain reaction (RT-qPCR). The protein levels were determined through enzyme linked immuno sorbent assay (ELISA) and western blot. The cell viability was detected through cell counting kit-8 (CCK-8) assay. Results: In this experiment, the animal model (rats induced by Streptozocin (STZ)) and cell model (Human renal glomerular endothelial cells (HRGEC) induced by HG) were built at first. FOSL2 improved the protein expression and knockdown of FOSL2 improved DN progression by reducing FBG, OGTT, HbA1c, 24 hours (h) urine protein (UP), Scr, and BUN levels (p < 0.001). In addition, FOSL2 suppression improved renal injury and inhibited cell apoptosis in DN rats (p < 0.001). Down-regulation of FOSL2 also reduced the inflammation and oxidative stress in DN rats (p < 0.001). In vitro experiments, FOSL2 inhibition enhanced cell viability (p < 0.001) and retarded cell apoptosis (p < 0.05), as well as reduced the inflammation (p < 0.05) and oxidative stress (p < 0.05) in HRGEC cells induced by HG. It was also identified that FOSL2 inhibition suppressed the activation of nuclear factor kappa-B (NF-κB) pathway in DN (p < 0.001). Conclusions: The findings in this study revealed that FOSL2 aggravated renal injury in DN by activating NF-κB signaling pathway. This discovery might offer a promising biomarker for DN treatment.