Gα13 induces preproET-1 gene expression via JNK

The endothelin B receptor (ET_BR) has been shown to mediate autoinduction of endothelin-1 (ET-1). We previously reported that the ET_BR interacts with Gα₁₃, a member of the heterotrimeric GTP-binding protein family. In the present study, we examined whether Gα₁₃, induces preproET-1 (ppET-1) gene transcription, which could result in ET-1 autoinduction in a renal epithelial cell line. We generated a reporter gene construct under control of the ppET-1 promoter region. The construct was transiently expressed in COS-7 cells. Transient expression of ET_BR increased the promoter activity of ppET-1 following treatment with 100 nmol/l of ET-1. Expression of Gα_13Q226L or Gα_qQ209L, constitutively active forms of Gα₁₃ and Gα_q, also activated the ppET-1 promoter. ET_BR-stimulated ppET-1 promoter activity was partially diminished by the expression of dominant negative forms of c-Jun N-terminal kinase (JNK1APF) or MAPK/ERK kinase (MEK_K97M). Expression of JNK1APF also inhibited Gα_13Q226L-induced ppET-1 promoter activation. These findings indicate that Gα₁₃ can induce ppET-1 gene expression through a JNK-mediated pathway. Our results also suggest that this Gα₁₃-coupled signaling pathway may play an important role in a sustained ET-1 autoinduction loop in various pathophysiological conditions.