Noscapine alleviates unilateral ureteral obstruction-induced inflammation and fibrosis by regulating the TGFβ1/Smads signaling pathways

Abstract

Renal fibrosis is a common pathway leading to progressive renal function loss in various forms of chronic kidney disease. Many fibrogenic factors regulate renal fibrosis; two key players are post-injury inflammation and transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation. Myofibroblast differentiation is tightly regulated by the microtubule polymerization. Noscapine, an antitussive plant alkaloid, is a potent microtubule-interfering agent previously identified as a potential anticancer compound. Here, we examined how noscapine affects renal fibrogenesis in an in vitro renal fibroblast model and an in vivo unilateral ureteral obstruction (UUO) model. UUO mice were intraperitoneally treated with noscapine at 1 day before UUO surgery and daily thereafter. At 7 days post-surgery, kidneys were collected for further analysis. To analyze whether noscapine inhibits downstream TGF-β1-related signaling, we pre-incubated NRK-49F fibroblasts with noscapine and then performed TGF-β1 stimulation. In UUO mice, noscapine attenuated extracellular matrix protein deposition and the expression levels of type I collagen, type IV collagen, α-smooth muscle actin, and fibronectin. In addition, noscapine decreased tubulointerstitial inflammation in UUO kidneys by reducing TLR2 expression, modulating NLRP3 inflammasome activation, reducing macrophage infiltration, and antagonizing the M2 macrophage phenotype. Furthermore, noscapine pre-incubation suppressed the TGF-β1-induced fibroblast-myofibroblast transformation by downregulating the TGF-β/Smads signaling pathways in NRK-49F cells. These results suggest that noscapine reduces tubulointerstitial inflammation and fibrosis in the kidneys of UUO mice and inhibits the fibroblast-myofibroblast transformation induced by TGF-β1. Noscapine is an over-the-counter antitussive that has been used safely for several decades. Therefore, noscapine is an attractive therapeutic agent for inhibiting renal tubulointerstitial fibrosis.

Keywords: Inflammation; Myofibroblast; Noscapine; Renal fibrosis; Unilateral ureteral obstruction.