Minnelide combined with Angptl3 knockout completely protects mice with adriamycin nephropathy via suppression of TGF-β1-Smad2 and p53 pathways

Minimal change disease (MCD) is the common type of nephrotic syndrome in children. There is an urgent need to explore new treatment methods as current treatments have many drawbacks and cause significant side effects. Our group found that Angiopoietin-like protein 3 (Angptl3) is closely related to renal disease and Angptl3 knockout significantly alleviated proteinuria in mice with adriamycin nephropathy (AN), however, some pro-teinuria was still present. Minnelide is a water-soluble prodrug of triptolide which has been used for the treat-ment of glomerular diseases. Therefore, this study aimed to investigate whether minnelide, combined with Angptl3 knockout, could completely protect mice with AN and its mechanism. AN was induced in B6;129S5 female mice by tail vein injection of 25 mg/kg of Adriamycin (ADR), and treatment with 200 ug/kg/d of minnelide. The results showed that minnelide combined with Angptl3 knockout completely reduced proteinuria and restored the foot processes in mice with AN. Moreover, in Angptl3 knockout mice with AN, minnelide restored the distribution of nephrin, podocin and cd2ap and reduced inflammatory factors (Tumor necrosis factor alpha (TNF-alpha), Interleukin-6 (IL-6) and Interleukin-1 beta (IL-1 beta)). Through RNA sequencing and related experi-ments, we found minnelide could ameliorate fibrosis and apoptosis by inhibiting TGF-beta 1-Smad2 and p53 pathways in Angptl3 knockout mice with AN, respectively. In Angptl3 knockout primary podocytes, triptolide alleviates ADR-induced decreases in nephrin, podocin and cd2ap, upregulation of Bax and downregulation of Bcl-2. Overall, our study shows that minnelide combined with Angptl3 knockout completely protects mice with AN by inhibiting the TGF-beta 1-smad2 and p53 pathways.

Automated summary

Minimal change disease (MCD) is the common type of nephrotic syndrome in children. Current treatments for MCD have many drawbacks and cause significant side effects, highlighting the need for new treatment methods. This study found that combining minnelide with Angptl3 knockout completely protected mice with adriamycin nephropathy (AN) by inhibiting the TGF-beta 1-smad2 and p53 pathways, reducing proteinuria and restoring foot processes. These findings suggest that minnelide combined with Angptl3 knockout could be a promising therapeutic approach for AN.