In the kidney a number of different tissue compartments

In the kidney, a number of different tissue compartments, including blood vessels, glomerulus, tubules and collecting ducts, secrete ET-1. ETA and ETB receptors coexist in the same Dorsomorphin receptor that secrete ET-1, but ETA and ETB also reside in juxtaglomerular and mesangial cells [28]. In polycystic kidney disease, ETA receptor expression is increased [29] and elevated ET-1 has been shown to contribute to renal ischemia and nephrotoxicity in animal models as well as in human disease [9], [30], [31], [32]. Indeed, several studies have demonstrated that ETA selective antagonists can protect against ischemia- and nephrotoxin-induced renal injury [33], [34], [35]. Stimulation of mesangial cells with ET-1 causes an autoinduction of a sixfold increase in ET-1 production through activation of the ETB receptor [36]. In general, the response to positive stimulus results in the transcription of ET-1 mRNA, with subsequent synthesis and secretion of ET-1 protein within minutes. The half-life of ET-1 mRNA is approximately 20min [4], [37], and the half-life of the protein in plasma is approximately 4–7min. Although, the half-life of mature ET-1 is short, an autocrine up-regulation mechanism in disease could induce elevated local concentrations in the kidney. ET-1 expression occurs in many carcinomas, including those arising in the kidney [38], prostate [7], ovary [5] endometrium [39], melanocyte [40], and central nervous system [41], [42], among others [43]. The endothelin axis expression in RCC appears to be dependent upon the tumor subtype [38]. In several carcinomas, ET-1 induces proliferation through the ETA receptor. Concomitantly, decreased ETB expression has been implicated in the pathogenesis of prostate [44], [45] and ovarian cancer [5]. The transcriptional regulatory region of the ETB receptor gene (EDNRB) contains a 5′ CpG island [21], and in human prostate cancer this region is commonly (70%) methylated [45], suggesting ETB downregulation occurs through suppression of transcription. ET-1, acting through ETA, has been shown to promote cell survival in benign stromal cell populations exposed to paclitaxel [46], [47]. Given the expression of ET-1 and the ET receptors in the normal as well as the cancerous kidney, it was our hypothesis the ET axis functions as a survival pathway in RCC. Therefore, we studied ET axis expression in RCC, and demonstrated that ET-1, acting through ETA and the downstream PI-3 kinase pathway, promotes cell survival.
Method and materials
Results
Discussion Given the potential role of ET-1 in tumorigenesis and the promise shown by select endothelin receptor antagonists in treating cancer, we investigated ET-1 signaling in RCC. All six RCC cell lines studied secreted levels of ET-1 at concentrations high enough to potentially activate receptors in an autocrine fashion. ETA expression was observed in all six cell lines and high affinity binding of ET-1 was evident in five of those lines. Furthermore, we demonstrated that ET-1 signaling in RCC induces protection from apoptosis through inducing the PI3-kinase pathway and activating Akt. Taken together, these data indicate that the survival effect of ET-1 is propagated via the ETA receptor. Identification of the profile of the ET signaling axis in RCC may promote new insight into potential therapeutic interventions.