Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Abstract

Percutaneous transluminal renal angioplasty/stenting (PTRAS) is frequently used to treat renal artery stenosis and renovascular disease (RVD); however, renal function is restored in less than one half of the cases. This study was designed to test a novel intervention that could refine PTRAS and enhance renal recovery in RVD. Renal function was quantified in pigs after 6 weeks of chronic RVD (induced by unilateral renal artery stenosis), established renal damage, and hypertension. Pigs with RVD then underwent PTRAS and were randomized into three groups: placebo (RVD+PTRAS), chronic endothelin-A receptor (ET-A) blockade (RVD+PTRAS+ET-A), and chronic dual ET-A/B blockade (RVD+PTRAS+ET-A/B) for 4 weeks. Renal function was again evaluated after treatments, and then, ex vivo studies were performed on the stented kidney. PTRAS resolved renal stenosis, attenuated hypertension, and improved renal function but did not resolve renal microvascular rarefaction, remodeling, or renal fibrosis. ET-A blocker therapy after PTRAS significantly improved hypertension, microvascular rarefaction, and renal injury and led to greater recovery of renal function. Conversely, combined ET-A/B blockade therapy blunted the therapeutic effects of PTRAS alone or PTRAS followed by ET-A blockade. These data suggest that ET-A receptor blockade therapy could serve as a coadjuvant intervention to enhance the outcomes of PTRAS in RVD. These results also suggest that ET-B receptors are important for renal function in RVD and may contribute to recovery after PTRAS. Using clinically available compounds and techniques, our results could contribute to both refinement and design of new therapeutic strategies in chronic RVD. Chronic renovascular disease (RVD) increases the risk of cardiovascular morbidity and mortality and may progressively induce renal injury, leading to ESRD. 1 Percutaneous transluminal renal angioplasty/stenting (PTRAS) is a frequently used therapeutic strategy to treat patients with chronic RVD. Targeting the renal stenosis is a logical choice for treating RVD, because the resolution of the vascular obstruction followed by restoration of blood flow to the site of injured tissues should play an important role to initiate successful repairing responses. The use of PTRAS in RVD grew significantly during the past 20 years, 2 with tremendous progress in successfully resolving renal stenosis and restoring blood flow (.95% of the cases). 3 However, despite the high technical success of PTRAS, improvement in renal function is still observed in a relatively small portion of the cases. 4 The reasons for the persistent poor outcomes after PTRAS in RVD are still unclear. Furthermore, the dissociation between the technical success of PTRAS and renal outcomes underscores a pressing need to identify more effective therapeutic strategies in RVD.Endothelin-1 (ET-1) is a powerful renal vasoconstrictor and mitogenic peptide that plays important roles in controlling BP and renal function.

Vascular Endothelial Growth Factor and Podocyte Protection in Chronic Hypoxia: Effects of Endothelin-A Receptor Antagonism

“…Recent preclinical and clinical studies support the notion that ET-A antagonism reduces proteinuria in CKD possibly by improving podocyte health 32 . Our previous studies in a swine model of RVD demonstrated that the ET-1/ET-A pathway is up-regulated and plays a prominent pathophysiological role in deteriorating RBF and GFR as well as in promoting inflammation and fibrosis 8, 9, 14 . Furthermore, blunted GFR and glomerulosclerosis in this model are associated with increased excretion of nephrin and attenuated expression of podocin, suggesting substantial podocyte damage.…”

“…Therefore, the current study was designed to test the hypothesis that renoprotection by ET-A antagonism may be driven by a distinct protection on podocytes steered by recovering VEGF bioavailability. To test our hypothesis and extend our previous in vivo findings 8, 9 by elucidating potential mechanisms of ET-1/ET-A-mediated podocyte injury and protection, human podocytes that were chronically exposed to hypoxia (to mimic the stenotic kidney environment in RVD 23 ) were treated with specific ET-A or ET-B antagonists. In addition, to determine whether protection of podocytes by ET-A antagonism is mediated by VEGF, a separate similar set of experiments was carried out after VEGF blockade.…”

“…Podocytes are both sources and targets of VEGF in autocrine and paracrine fashion, express VEGF receptors 19 and also express ET-A and B receptors 20 . Our recent studies showed that the excretion of nephrin from the stenotic kidney (a marker suggestive of podocyte injury) is exacerbated in the swine model of RVD but is reduced by ET-A antagonism 9 . Furthermore, the stenotic kidney has a significant decrease in the expression and availability of VEGF 21, 22 that is largely restored after ET-A antagonism 8, 9, 14 .…”

“…Our recent studies showed that the excretion of nephrin from the stenotic kidney (a marker suggestive of podocyte injury) is exacerbated in the swine model of RVD but is reduced by ET-A antagonism 9 . Furthermore, the stenotic kidney has a significant decrease in the expression and availability of VEGF 21, 22 that is largely restored after ET-A antagonism 8, 9, 14 . Therefore, the current study was designed to test the hypothesis that renoprotection by ET-A antagonism may be driven by a distinct protection on podocytes steered by recovering VEGF bioavailability.…”

“…A frequent etiology of CKD is chronic renovascular disease (RVD), which affects between 9–11% of the general population and can deteriorate renal function, lead to CKD, and progress to end-stage renal disease 3–5 . Our previous studies in a swine model of chronic RVD (induced by unilateral renal artery stenosis) showed that the stenotic kidney develops a progressive deterioration of hemodynamics, filtration, and tubular function, accompanied by a significant vascular rarefaction and the development of albuminuria, glomerulosclerosis, and tubule-interstitial fibrosis 6–9 .…”