Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension

Abstract

Abstract-We have recently found in male homozygous hypertensive Ren-2 transgenic rats (TGRs) fed a high-salt diet that early onset selective endothelin (ET) A (ET A ) or nonselective ET A /ET B (ET B ) receptor blockade improved survival rate and reduced proteinuria, glomerulosclerosis, and cardiac hypertrophy, whereas selective ET A receptor blockade also significantly attenuated the rise in blood pressure. Because antihypertensive therapy in general is known to be more efficient when started at early age, our study was performed to determine whether onset of ET receptor blockade at a later age in animals with established hypertension will have similar protective effects as does early-onset therapy. Endothelin (ET)-1 is known to be one of the most powerful vasoconstrictors 5,6 and also a mitogen in vivo and in vitro. 7 The beneficial effects of ET receptor blockers in modulating target organ damage are attributed to their antiproliferative actions. 8 Numerous studies have shown that the ET system plays an important role in the pathogenesis of high blood pressure (BP) in salt-sensitive models of hypertension and in associated end-organ damage. 9 For the detrimental effects of ET-1 in the development of hypertension, activation of ETA (ET A ) receptors may be responsible, whereas the role of ET B (ET B ) receptors may be the mediation of peripheral vasorelaxation and the renal tubular natriuresis. Nonselective blockade, therefore, inhibits not only the deleterious effects of ET-1 mediated by ET A receptors but also concomitantly blocks its antihypertensive effects mediated by ET B receptors. However, because at present only conflicting data regarding selective ET A and nonselective ET A/B receptor blockade are available, the relative beneficial effects of selective versus nonselective ET receptor blockade remain to be elucidated.Several lines of evidence indicate that Ang II stimulates the release of ET-1, and it is known that the ET system plays an important role in the pathogenesis of hypertension and accompanying end-organ damage in salt-dependent and in Ang IIdependent models of hypertension induced by exogenous administration of Ang II. 10 Dietary sodium plays an important role in the pathogenesis of hypertension not only in humans 11 but also in salt-sensitive

Persistent antihypertensive effect of aliskiren is accompanied by reduced proteinuria and normalization of glomerular area in Ren-2 transgenic rats

“…Increased workload then leads to podocyte damage. Moreover, it is known that ultrastructural changes appear at least 3 wk after the immunologic changes (23,35), and our results on podocyte injury in Ren-2 TGR (25) have shown that ultrastructural changes of podocytes precede morphological changes seen by light microscope.…”

“…As has been previously reported (7,25), TGR evolve proteinuria (and albuminuria) at the age of 8 -10 wk; therefore no evaluation of this parameter was included in our prevention protocol. Renoprotective effect of aliskiren has repeatedly been confirmed not only in humans (28) but also in a model of diabetic nephropathy in Ren-2 animals (7) and in double transgenic rats (5,29).…”

The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses

“…Additionally, reduced ETB-mediated clearance would probably increase plasma ET-1 levels [21]. In agreement, pre-clinical data show that selective ETA antagonism may be preferential to nonselective blockade in CKD [41,42].…”

The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

“…24 However, in adult hypertensive Ren-2 transgenic rats on a high-salt diet, no differences regarding proteinuria and renal histology between both compounds were found. 25 Furthermore, the dual ET A /ET B receptor blocker macitentan that was used in the present study reduced renal injury in the streptozotocininduced diabetic rat. 13 Taken together, these findings provide strong evidence that dual ET A /ET B receptor blockade, like selective ET A antagonism, exerts renal protective effects in various models of renal injury.…”