Endothelin Signaling and Actions in the Renal Mesangium

Endothelins (ETs), and particularly ET-1, activate a complex network of interconnected signaling cascades in mesangial glomerular cells, which play an important role in the physiology and pathophysiology of the glomerulus. Excessive stimulation of ET-1 production by mesangial cells results in activation of a wide variety of signaling pathways in the renal mesangium, which is at least partially responsible for glomerular damage in the setting of diabetes, hypertension, and glomerulonephritis. Mesangial cells express both types of ET receptors (ET(A)-R and ET(B)-R), which are G protein-coupled receptors. ET-1 induces mobilization of Ca(2+); activation of phospholipases A, C, and D; activation of protein kinase C; GTP-loading of several families of small GTPases; and activation of intracellular tyrosine kinases resulting in protein tyrosine phosphorylation of adaptor, scaffolding, and signaling proteins. ET-1-triggered posttranslational modification of signaling molecules sets the base for the formation of multiunit signaling complexes which define the specificity of ET signaling. Long-term effects of ET-1 are also mediated via increased expression of particular signaling proteins. It is likely that ET-1 acts via ET(A)-R to trigger the contraction of mesangial cells, which decreases glomerular filtration area and reduces the glomerular filtration rate, promoting impaired renal function. Proliferation of mesangial cells is observed in the progress of several types of glomerulonephritis. ET-1 is a potent mitogen of mesangial cells and the ability of ET-1 to support mesangial cell proliferation is likely to be associated with both recruitment of cytoplasmic tyrosine kinases which activate the Shc-Sos-Ras-Raf-MEK-ERK signaling pathway and transactivation of the EGF receptor. The guanine nucleotide exchange factor βPix and the adaptor protein p66(Shc) are important players in Akt-independent inactivation of FOXO3a transcription factor. This results in the depletion of the inhibitor of cell cycle progression p27(kip1), and promotion of mesangial cell proliferation. Plentiful evidence suggests an essential role of ET-1-signaling and action in the renal mesangium for renal biology and pathobiology.