Shen-Qi-Di-Huang Decoction induces autophagy in podocytes to ameliorate membranous nephropathy by suppressing USP14.

Abstract

Ethnopharmacological relevance: Shen-Qi-Di-Huang decoction (SQDHD) is a renowned decoction in traditional Chinese medicine, dating back to the Qing Dynasty. SQDHD has been widely applied in treating renal diseases, including Membranous nephropathy (MN), with its proven positive clinical outcomes. Nevertheless, the precise mechanism by which SQDHD exerts its therapeutic effects on MN remains uncertain.

Aim of the study: The present research aimed to observe whether SQDHD promotes podocyte autophagy by inhibiting USP14 to increase the K63 ubiquitination of Beclin1, thereby improving MN.

Materials and methods: An MN model was established in rats using Passive Heyman Nephritis (PHN) to explore the underlying mechanisms in vivo. The kidney function parameters were evaluated, and the histomorphology of glomerular tissues was examined. Autophagy-related protein expression was assessed using immunofluorescence staining and western blotting assays. Co-immunoprecipitation (Co-IP) was used to detect the K63 ubiquitination of Beclin1. MPC5 cells were treated in vitro with serum obtained from several rat groups. Subsequently, the expression of autophagy-related proteins, formation of autophagosomes, expression of USP14, and K63 ubiquitination of Beclin1 were quantified.

Results: Our results demonstrated that SQDHD intervention reduced urinary protein levels, mitigated podocyte damage in MN model rats, and improved kidney tissue pathology. Furthermore, in vitro and in vivo data revealed that SQDHD therapy significantly increased podocyte autophagy, decreased USP14 expression, and raised Beclin1's K63 ubiquitination.

Conclusion: These results provided a scientific rationale supporting the ability of SQDHD to substantially alleviate MN progression by inducing podocyte autophagy through the inhibition of USP14 expression.