Endothelin peptides and compensatory growth of renal cells

Endothelins are paracrine or autocrine peptides that regulate diverse aspects of renal function. In addition to their potent vasoconstrictor activity, recent evidence suggests that endothelin-1 is a growth factor for renal cells. Different forms of renal injury markedly upregulate endothelin-1 secretion, which is postulated to contribute to compensatory renal growth. Similar roles have been hypothesized for other vasoactive peptides, such as angiotensin II and arginine vasopressin. New information has recently emerged regarding pathways of mitogenic signaling linking activation of endothelin receptors to changes in gene expression. ETA receptor subtypes activate downstream effectors, such as protein kinase C, protein tyrosine kinases of the src gene family, and mitogen-activated protein kinases. These cytosolic effectors in turn lead to altered programs of gene expression by activating, among others, AP-1 and serum response factor transcription factors. In addition, recent studies in organisms amenable to genetic analysis, such as Drosophila, Dictyostelium, and yeast, are providing important clues to effector mechanisms employed by vasoactive peptide receptors in higher organisms. Information on the molecular mechanisms for mitogenic signaling by endothelin receptors might be used to gain insight into the pathogenesis of compensatory renal growth and the development of novel therapeutic strategies.