Glomerular hypertrophy and hyperfiltration are the two major pathological characteristics of the early stages of diabetic nephropathy (DN), which are respectively related to mesangial cell (MC) proliferation and a decrease in calcium influx conducted by canonical transient receptor potential cation channel 6 (TRPC6). The marked increase in the production of reactive oxygen species (ROS) induced by hyperglycemia is the main sponsor of multiple pathological pathways in DN. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of ROS production in MCs. Astragaloside IV (AS-IV) is an active ingredient of Radix Astragali which has a potent antioxidative effect. In this study, we aimed to investigate whether high glucose (HG)-induced NADPH oxidase activation and ROS production contribute to MC proliferation and the downregulation of TRPC6 expression; we also wished to determine the effects of AS-IV on MCs under HG conditions. Using a human glomerular mesangial cell line, we found that treatment with AS-IV for 48 h markedly attenuated HG-induced proliferation and the hypertrophy of MCs in a dose-dependent manner. The intracellular ROS level was also markedly reduced following treatment with AS-IV. In addition, the enhanced activity of NADPH oxidase and the expression level of NADPH oxidase 4 (Nox4) protein were decreased. Treatment with AS-IV also inhibited the phosphorylation level of Akt and IκBα in the MCs. In addition, TRPC6 protein expression and the intracellular free calcium concentration were also markedly reduced following treatment with AS-IV under HG conditions. These results suggest that AS-IV inhibits HG-induced mesangial cell proliferation and glomerular contractile dysfunction through the NADPH oxidase/ROS/Akt/nuclear factor-κB (NF-κB) pathway, providing a new perspective for the clinical treatment of DN.
- Astragaloside IV
- Diabetic nephropathy
- Human mesangial cells
- Nicotinamide adenine dinucleotide phosphate oxidase
- Reactive oxygen species