Triptolide delays disease progression in an adult rat model of polycystic kidney disease through the JAK2-STAT3 pathway

Abstract

The aim of our current study was to investigate the long-term effect and the mechanism of triptolide in an adult nonorthologous rat model of polycystic kidney disease (PKD). Male wild-type (+/+) and Cy/+ cystic Han:SPRD rats were treated with vehicle or triptolide from 4 to 16 wk of age. Rats were killed at 16 wk of age for blood, urine, and organ collection. Human-derived WT9–12 PKD cells were treated with triptolide with or without IL-6 pretreatment. Cell proliferation, apoptosis, and cytotoxicity were determined. Western blotting and immunohistochemistry analysis were performed to evaluate the activation of IL-6-JAK2-STAT3 pathway. Renal function was protected by 12 wk of triptolide treatment in cystic Han:SPRD rats as shown by reduced blood urea nitrogen, serum creatinine, and proteinuria levels. Cyst and kidney growth were also retarded by triptolide treatment in Cy/+ rats. We further found that the proliferation index was reduced by triptolide in cystic rats, which was correlated with the reduced expression of IL-6/IL-6 receptor, decreased phosphorylation of JAK2-STAT3, and increased expression of suppressor of cytokine signaling 3 (SOCS3). The inhibitory effect of triptolide was further studied in WT9–12 cells. Triptolide inhibited cell proliferation and the activation of JAK2-STAT3 pathway in PKD cells, but it increased the expression of SOCS3. Pretreatment with IL-6 attenuated the inhibitory effect of triptolide on STAT3 phosphorylation. Our study revealed a long-term beneficial effect of triptolide in PKD that was probably through inhibition of the JAK2-STAT3 pathway.