Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease

Abstract

Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg(-1)·day(-1)) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD.

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

“…Body weights were similar among the groups, whereas circulating ET-1 levels were similarly elevated in all pigs after 6 weeks of RVD (Table 1). Serum creatinine was increased as renal blood flow (RBF) and GFR substantially decreased (between 30% and 50%) compared with normal controls, which we have previously observed [10][11][12] (Figure 3, Table 1). The deterioration in renal hemodynamics and function was evident at baseline and also after endothelium-dependent challenge by acetylcholine (data not shown), suggesting a significant renal microvascular (MV) endothelial dysfunction.…”

“…12,24,25 We recently showed the important role that the ET pathway plays on the progressive injury of the stenotic kidney in RVD, which is mainly mediated by the ET-A receptor. 10,11 Blockade of the Parameters were obtained 4 weeks after PTRAS and placebo/ET receptor blocker therapy at 10 weeks. RVR, renal vascular resistance.…”

“…RVR, renal vascular resistance. a ET-A receptor, indeed, significantly improved renal function, decreased MV and tissue damage, and improved MV proliferation and repair, even without resolving renal artery stenosis, 10,11 suggesting that renal injury in the stenotic kidney is progressive but potentially reversible through targeted ETantagonism. Thus, this model offers a unique opportunity to determine whether therapeutic actions of ET-A receptors blockade could play a role in renal outcomes after PTRAS in RVD.…”

“…We observed a significant and persistent reduction in RBF and GFR in the stenotic kidney accompanied by a marked cortical and medullary MV rarefaction and renal fibrosis (Table 3), which concurred with our previous reports in this model. 10,11,15,16 …”

“…8,9 Using a well established swine model of chronic RVD, we recently showed that the ET-1/ET-A pathway is upregulated in RVD both systemically and in the stenotic kidney and that chronic ET-A blockade in experimental RVD improves renal function, decreases renal damage, and protects the renal microvasculature of the stenotic kidney. 10,11 These studies showed the role of the ET-1/ET-A pathways in the development and the progression of renal injury in RVD. We also showed that PTRAS in this model of RVD is feasible and effective in resolving the stenosis while mimicking the inadequate responses observed in human RVD.…”