Inhibition of ferroptosis of renal tubular cells with total flavones of Abelmoschus manihot alleviates diabetic tubulopathy

Anat Rec (Hoboken). 2022 Nov 28. doi: 10.1002/ar.25123. Online ahead of print.

Abstract

Ferroptosis-related renal tubular lesions play important roles in diabetic kidney disease (DKD) progression, and these pathophysiological responses are collectively described as diabetic tubulopathy (DT), which lacks an effective treatment. Total flavones from Abelmoschus manihot (TFA), a natural extract that extensively used in patients with chronic kidney disease, has been used for treatment of renal tubular injury in DKD; however, whether TFA alleviates DT and its potential mechanisms remain unclear. Hence, we investigated the effects of TFA, compared to dapagliflozin, in DT management both in vivo and in vitro, using a DKD rat model and the NRK-52 E cells. Following modeling, the DKD rats received TFA, dapagliflozin, or vehicle for 6 weeks. For the in vitro research, the NRK-52 E cells were exposed to advanced glycation end products (AGEs) plus ferrostatin-1 (Fer-1), dapagliflozin, or TFA. Changes in biochemical parameters and renal tubular injury were analyzed in vivo, while changes in ferroptosis of renal tubular cells and the ferroptosis-related proteins expression were analyzed both in vivo and in vitro. We found that TFA and dapagliflozin improved biochemical parameters, renal tubular injury, and ferroptosis in the DKD rats. Moreover, TFA and dapagliflozin inhibited ferroptosis by ameliorating iron deposition, lipid peroxidation capacity, and ferroptosis-related proteins expression in vitro, which was similar to the effects of Fer-1. Collectively, this study demonstrated that TFA treated DT in a manner similar to dapagliflozin by inhibiting ferroptosis of renal tubular cells via improving iron deposition and antioxidant capacity. Our findings provide new pharmacological evidence for TFA application in DT treatment.

铁死亡相关的肾小管损伤在糖尿病肾脏疾病(DKD)进展中发挥着重要作用,这些病理生理学的变化被统称为糖尿病肾小管病(DT),缺乏有效的治疗。黄蜀葵花总黄酮(TFA)作为一个广泛用于慢性肾脏病患者的天然提取物已被应用于DKD肾小管损伤的治疗,但是,TFA是否能减轻DT以及它的潜在机制仍不清楚。因此,在DT的体内外干预性研究中,我们用DKD大鼠模型和NRK-52E细胞观察了TFA的作用,并与达格列净对比。在造模后,DKD大鼠接受了6周的TFA、达格列净或安慰剂的干预。在体外研究中,NRK-52E细胞与晚期糖基化终末产物(AGEs)、ferrostatin-1(Fer-1)、达格列净以及TFA共培养。在体内,生化参数和肾小管细胞损伤的变化得到了分析。在体内外研究中,肾小管细胞铁死亡和铁死亡相关蛋白表达的变化也得到了分析。我们发现,TFA和达格列净改善了DKD大鼠生化参数、肾小管损伤和铁死亡。此外,TFA和达格列净在体外通过改善铁超载、脂质过氧化以及铁死亡相关蛋白表达而抑制了铁死亡,这些作用类似于Fer-1。总之,本研究阐明,TFA与达格列净类似,通过抑制铁死亡和改善铁超载、脂质过氧化而干预了DT。我们的发现为TFA在DT治疗上的应用提供了新的药理学依据。.

Keywords: diabetic tubulopathy; ferroptosis; renal tubular injury; total flavones of Abelmoschus manihot; 糖尿病肾小管病; 肾小管损伤; 铁死亡; 黄蜀葵花总黄酮.