Tanshinone IIA reduces tubulointerstitial fibrosis by suppressing GSDMD-mediated pyroptosis

Context: Tanshinone IIA (Tan IIA), a bioactive compound derived from the traditional Chinese herb Salvia miltiorrhiza (Family Lamiaceae, Authority Bunge), is well-known for its protective effects in various kidney diseases. However, its role in obstructive nephropathy has not been thoroughly investigated.

Objective: This study aimed to explore the protective effects of Tan IIA in a mouse model of unilateral ureteral obstruction (UUO) and to elucidate the cellular and molecular mechanisms underlying these effects.

Materials and methods: Gasdermin D (GSDMD) knockout mice and their wild-type (WT) littermates underwent UUO surgery, with Tan IIA treatment administered 24 h prior. Human proximal tubular cells (HK-2 cells) were treated with TGF-β1 to induce fibrosis (50 ng/mL for 24 h), followed by Tan IIA treatment (5 μM) for an additional 3 h.

Results: Tan IIA significantly reduced the expression of extracellular matrix (ECM) components, including Collagen I, α-smooth muscle actin (α-SMA), vimentin and fibronectin, in UUO mice. Tan IIA attenuated GSDMD-mediated Pyroptosis. However, in GSDMD knockout mice subjected to UUO, the protective effects of Tan IIA on ECM gene expression and Collagen deposition in the tubular interstitium were reduced. In vitro studies showed that Tan IIA reduced GSDMD activation and fibronectin protein expression in HK-2 cells.

Discussion and conclusions: Tan IIA may mitigate GSDMD-mediated Pyroptosis in renal tubular epithelial cells (RTECs) and reduce kidney fibrosis, highlighting its potential as a therapeutic strategy to prevent the progression of kidney disease after ureteral obstruction.

Chinese herbal medicine; Gasdermin D; cell death; chronic kidney disease; pyroptosis; unilateral ureteral obstruction.