Astragalus polysaccharide alleviates angiotensin II‐induced glomerular podocyte dysfunction by inhibiting the expression of RARRES1 and LCN2

Abstract Podocyte loss is a predictor of kidney disease development, including diabetic nephropathy. Astragalus polysaccharide (APS) was considered a renoprotective drug, whereas the mechanisms operated by APS on podocyte dysfunction are rarely mentioned. This study aims at the mechanistic underlying of APS on angiotensin II (Ang II)‐induced podocyte dysfunction. Mouse glomerular podocytes MPC5 were induced with Ang II, the morphologic changes were observed and nephrin, desmin and Wilms’ tumour protein‐1 (WT‐1) levels were determined. The MPC5 cells were treated with APS (50, 100 and 200 μg/mL) and transduced with retinoic acid receptor responder protein 1 (RARRES1) overexpression vectors. The expression of RARRES1, lipocalin‐2 (LCN2), nephrin and desmin was tested, MPC5 cell viability and apoptosis were evaluated, and the levels of an endocytotic receptor megalin, Bcl‐2, Bax, interleukin (IL)‐6, IL‐1β and tumour necrosis factor (TNF)‐α were assessed. The binding of RARRES1 to LCN2 was predicted and verified. Mice were infused with Ang II to evaluate histopathological alterations and 24‐h urinary albumin content. Ang II induction suppressed MPC5 cell viability, reduced the expression of nephrin, WT‐1, megalin and Bcl‐2, and augmented the expression of desmin, Bax, IL‐6, IL‐1β and TNF‐α, which were significantly nullified by APS treatment. RARRES1 interacted with LCN2, and APS treatment inhibited RARRES1 and LCN2 expression in a dose‐dependent manner, thereby alleviating Ang II‐induced podocyte dysfunction. Ang II infusion in mice facilitated pathological alterations in renal tissues and increased urinary albumin content, which were attenuated after APS treatment. Overall, APS treatment alleviated Ang II‐induced podocyte dysfunction by inhibiting RARRES1/LCN2 expression and blocked kidney injury development in vivo.