Disparate effects of single endothelin-A and -B receptor blocker therapy on the progression of renal injury in advanced renovascular disease

Abstract

We hypothesized that chronic specific endothelin (ET)-A receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed-tomography. All pigs with renovascular disease were divided such that 7 were untreated, 7 were treated with ET-A blockers, and 5 were treated with ET-B blockers. Four weeks later, all pigs were re-studied in vivo, then euthanized and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. RBF, GFR, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation and fibrosis in the stenotic kidney. These effects were functionally consequential since ET-A blockade improved single kidney microvascular endothelial function, RBF, and GFR, and decreased albuminuria.

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.…”

“…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.…”

“…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.…”

“…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.…”