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Background: The increased influx of free fatty acids (FFAs) into the kidney is a risk factor for diabetes nephropathy (DN). In the present study we investigated the effects of astragaloside IV (AS-IV) on FFA-induced lipid accumulation, oxidative stress, and activation of TGF-β1 signaling in human glomerular mesangial cells (HMCs)., Methods: A DN model was induced in Sprague Dawley rats by the administration of a high-fat diet and streptozocin, and HMCs were stimulated with palmitate. Lipid accumulation and FFA uptake were detected using Oil Red O and BODIPY™ FL C 16 staining, respectively. The expression levels of TGF-β1, p-Smad2/3, FN, Col4 A1, NOX4, p22phox, and CD36 were evaluated by western blotting or immunofluorescence/immunohistochemistry. The level of reactive oxygen species (ROS) was detected using 2',7'-dichlorofluorescein diacetate and dihydroethidium., Results: Exposure to palmitate induced marked lipid accumulation in HMCs, whereas co-treatment with AS-IV significantly attenuated this phenomenon. Moreover, AS-IV suppressed palmitate-induced expression of TGF-β1, p-Smad2/3, FN, Col4 A1, NOX4, and p22phox, in addition to ROS production. Notably, AS-IV reduced the palmitate-induced expression of CD36 in HMCs and DN rats. Treatment of HMCs with the CD36 inhibitor, sulfo-N-succinimidyl oleate (SSO), significantly attenuated FFA uptake, oxidative stress, and fibrosis. Nevertheless, the combined use of SSO and AS-IV did not enhance the efficacy., Conclusion: AS-IV inhibited palmitate-induced HMCs oxidative stress and fibrosis via the downregulation of CD36 expression, mediating FFA uptake and lipid accumulation., (Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Renal tubular injury is associated with the development of diabetic nephropathy (DN) and the end-stage renal disease (ESRD). Free fatty acids (FFAs)-associated lipotoxicity contributes to injury of proximal renal tubular epithelial (HK-2) cells in diabetes. Palmitic acid (PA) which is the most abundant saturated fatty acid in FFAs is closely associated with the gradual decline of renal function. Astragalosides IV (AS-IV) has a variety of pharmacological effects such as anti-inflammation and anti-oxidation. In the current study, we investigated the effects of AS-IV on PA-induced apoptosis of HK-2 cells and the underlying mechanisms. The results showed that AS-IV (10, 20, 40 μmol/L) could alleviate PA-induced apoptosis of HK-2 cells. We found that AS-IV reduced the expression of Bax and cleaved-caspase3, but increased the expression of Bcl-2 and phosphorylated Nrf2 in HK-2 cells. Moreover, AS-IV reduced the level of reactive oxygen species (ROS) in the cells. Our study suggests that AS-IV could protect against PA-induced apoptosis in HK-2 cells by inhibiting ROS generation and apoptotic protein expression. This study may provide a new theoretical option for the patients with type 2 diabetes., (Copyright © 2018. Published by Elsevier Masson SAS.)