Life and Death of Podocytes: Not Only a Matter of Vascular Endothelial Growth Factor

ment of the ET-1 pathway in chronic RVD, examining the effects of the ET A and ET B receptor antagonism on podocyte integrity and survival in the ischemic kidney [4] . Podocytes are highly specialized epithelial cells constituting the outer layer of the glomerular filtration barrier, and their dysfunction and loss are hallmarks of proteinuric renal disease [5] . Notably, podocytes possess a fully functional ET system, and evidence has highlighted the role of ET-1 in promoting structural and functional alteration of these cells in renal disease [5] . Mindful of the previously reported in vivo effects of ET-1 blockade, in the present work, the authors exploited a hypoxic in vitro approach that offered the opportunity to dissect the mechanisms underlying podocyte injury and recovery by mimicking the renal environment of chronic RVD. They analysed human podocytes that were exposed to chronic hypoxia and treated with either an ET A or ET B receptor antagonist. Hypoxia decreased the podocyte count, while it increased the number of cells displaying morphological changes suggestive of apoptosis, such as nuclear condensation and fragmentation. These effects paralleled the decreased expression of vascular endothelial growth factor (VEGF) and slit diaphragm-associated proteins podocin and nephrin. Furthermore, hypoxic podocytes displayed increased expression of the anti-VEGF soluble receptor s-Flt 1 and of pro-apoptotic mediators, including BAX, p53 and SMAC. Treatment with ET A receptor antagonist Renovascular disease (RVD) comprises a variety of conditions that alter the arterial supply of the kidney, inducing hypertension and affecting renal function, ultimately leading to chronic kidney disease. Although renal artery interventions are frequent therapeutic strategies for treating RVD, many patients derive little net benefit from them. This creates an urgent need for the identification of disease mediators that could be targeted to prevent irreversible injury in the post-stenotic kidney or other complications. Soon after its discovery, endothelin-1 (ET-1) was identified as a key factor in controlling kidney function and promoting renal disease progression [1] , due to its vasoconstrictive action and mitogenic property. More recently, the role of ET-1 in fostering renal injury in chronic RVD was put forward, with a particular focus on the roles of ET receptors, ET-1 type A (ET A ) and ET-1 type B (ET B ) [2, 3] . Results from these studies documented the disparate effects of the selective antagonism of ET A receptor compared to dual ET A /ET B [3] or ET B receptor [2] blockade in a porcine model of chronic RVD. While ET A receptor antagonist improved hypertension, microvascular rarefaction and renal injury, dual ET A /ET B blunted the therapeutic effects, and single ET B receptor inhibition was ineffective. In the current issue of the American Journal of Nephrology , Harvey et al. further investigated the involvePublished online: March 2, 2016 Nephrology American Journal of