Arrestin(g) podocyte injury with endothelin antagonism.

Proteinuria is a major pathologic feature of a wide variety of progressive CKD. Even if it is accompanied by a normal GFR, proteinuria indicates significant kidney dysfunction and its presence has been incorporated into definitions for CKD.1 Because proteinuria is an independent risk factor for CKD, it is imperative to determine the mechanisms leading to its development. Current antiproteinuric therapy reliesmainly on reninangiotensin inhibition, but this is only partially successful and novel treatments are urgently needed.2 In this issue of JASN, Buelli et al. examine how endothelin-1 (ET-1) mediates podocyte injury/dysfunction.3 The endothelins are a family of vasoactive peptides with a variety of roles in human disease, with ET-1 being the most relevant in kidney pathology. ET-1 binds to two receptors, endothelin A and endothelin B receptors (ETAR and ETBR, respectively). In general, ETAR is responsible for vasoconstrictive and pathologic actions of ET-1, whereas ETBR governs protective vasodilatory functions. Therefore, selective blockade of ETAR with pharmacologic agents such as sitaxsentan and atrasentan has been explored as a renoprotective therapy, and positive results in reducing proteinuria were demonstrated in a variety of kidney diseases, including diabetic nephropathy.4 ET-1 was previously shown to play a critical role in the development of metastatic ovarian cancer by promoting the formation of an ETAR/b-arrestin/Src kinase complex in an autocrine manner, which leads to stabilization and upregulation of b-catenin and Snail transcriptional regulators. Such actions resulted in an epithelial-to-mesenchymal transition of these cancer cells, increasing their invasive potential.5 These findings are relevant for proteinuric kidney disease because podocytes undergo a similar transition to a more motile phenotype in crescentic renal diseases.6 Drawing upon this comparison with tumor cell behavior, the authors examined the role of ET-1 in podocyte phenotypic changes. Utilizing in vitro podocyte cultures, they found that ET-1 does in fact induce an epithelial-to-mesenchymal transition–like event, with concomitant downregulation of the podocyte marker synaptopodin and upregulation of a-smooth muscle actin. These changes were associated with increased motility in a wound healing assay. Turning to in vivo studies, the authors utilized the adriamycin nephropathymodel inmice. Thismodel recapitulates proteinuric renal disease, with features similar to human FSGS.7 The authors demonstrated a loss of Wilms tumor 1 positivity in glomeruli after adriamycin administration, and scanning electron microscopy revealed markedly abnormal foot processes and enlarged podocytes. Treatment with the ETAR inhibitor sitaxsentan ameliorated these morphologic changes. These results are perhaps not unexpected considering the antiproteinuric effect of ETAR inhibition. Themore interesting and novel finding in this study is the elucidation of the mechanism underlying this protection. It appears that, similar to ovarian cancer cells, ET-1–mediated podocyte injury involves the activation of a protein known as b-arrestin-1. The arrestins are ubiquitous proteins that participate in functions as diverse as G-protein signaling and endocytosis. They are also capable of acting as scaffold proteins that can gather various intracellular proteins into close proximity to initiate complex signaling pathways.8 Buelli et al. have performed a careful interrogation of the ET-1–triggered signaling events and demonstrate that ET-1 ligation to its receptor in podocytes leads to induction of b-arrestin-1 and promotes the formation of a multicomponent complex containing b-arrestin-1, ETAR, and Src kinase. b-Arrestin-1 is also upregulated in hyperplastic lesions in samples from adriamycin-treated rodents and in human crescentic glomerular disease biopsies, suggesting clinical relevance for the activation of this signaling complex. Interestingly, assembly and activation of the ETAR/b-arrestin/Src complex results in the transactivation of the EGF receptor, which triggers downstream signaling that ultimately leads to the stabilization and increased activity of b-catenin. b-Catenin is a key transcriptional regulator that is essential for normal kidney development, but its activity is largely silenced in adult kidneys. However, growing evidence implicates hyperactive b-catenin activity in the pathogenesis of a variety of kidney diseases. As a transcriptional regulator, b-catenin controls, directly or indirectly, the expression of a battery of downstream target genes such as Snail1, plasminogen activator inhibitor-1, and matrix metalloproteinase-7, as well as multiple components of the renin-angiotensin system, all of which are highly relevant to kidney injury. Earlier studies showed that b-catenin activity is upregulated specifically in glomerular podocytes in various proteinuric kidney diseases such as FSGS and diabetic nephropathy and that genetic Published online ahead of print. Publication date available at www.jasn.org.