ETA receptor blockade induces fibrosis of the clipped kidney in two-kidney-one-clip renovascular hypertensive rats

Hocher, Berthold; George, Ines; Diekmann, Fritz; Zart, Rüdiger; Rebstock, Johannes; Schwarz, Anja; Thöne-Reineke, Christa; Neumayer, Hans‐H.; Bauer, Christian

doi:10.1097/00004872-200018120-00015

Cited by 34 publications

(28 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ischemia on its own is a well-known pro-fibrotic stimulus (for review, see reference 33). A very recent study also demonstrates that long-term treatment with an ETA receptor antagonist in rats with two kidney-one clip (2K-1C) renovascular hypertension increases fibrosis in the clipped (ischemic) kidney (15).…”

Section: Discussionmentioning

confidence: 94%

“…For pathohistologic evaluation, all samples were embedded in paraffin, cut in 3-m sections, and submitted to hematoxylin-eosin, Sirius red, and periodic acid-Schiff (PAS) staining and analyzed as recently described (15). The severity of interstitial matrix deposition was evaluated after Sirius red staining using a computer-aided imageanalyzing system.…”

Section: Histologic Evaluationmentioning

confidence: 99%

“…Glomerulosclerosis was defined by the presence of PAS-positive material within the glomeruli. To consider differences in the degree of glomerulosclerosis, a semiquantitative scoring system was used as recently described (15). All tissue samples for scoring were evaluated independently by two investigators without prior knowledge of the group to which the rats belonged.…”

Section: Histologic Evaluationmentioning

confidence: 99%

See 2 more Smart Citations

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Hocher¹,

Kalk²,

Slowinski³

et al. 2003

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Abstract. Tissue concentrations of ET-1 are markedly elevated in the kidneys of Han:Sprague-Dawley (Han:SPRD) rats, a model of human autosomal dominant polycystic kidney disease (ADPKD). This study analyzed whether disease progression might be attenuated by endothelin receptor antagonists. Heterozygous Han:SPRD rats received an ETA receptor antagonist (LU 135252), a combined ETA/ETB receptor antagonist (LU 224332), or placebo for 4 mo. Glomerulosclerosis, protein excretion, and GFR remained unchanged, whereas interstitial fibrosis was enhanced by both compounds. BP was not reduced by both compounds in Han:SPRD rats. Renal blood flow (RBF) decreased in ADPKD rats treated with the ETA receptor antagonist. Long-term ETA receptor blockade furthermore increased markedly the number of renal cysts (ADPKD rats, 390 Ϯ 119 [cysts/kidney section Ϯ SD]; LU 135252-treated APKD rats, 1084 Ϯ 314; P Ͻ 0.001), cyst surface area (ADPKD rats, 7.97 Ϯ 2.04 [% of total section surface Ϯ SD]; LU 135252-treated ADPKD rats, 33.83 Ϯ 10.03; P Ͻ 0.001), and cell proliferation of tubular cells (ADPKD rats, 42.2 Ϯ 17.3 [BrdUpositive cells/1000 cells]; LU 135252-treated ADPKD rats, 339.4 Ϯ 286.9; P Ͻ 0.001). The additional blockade of the ETB receptor attenuated these effects in Han:SPRD rats. Both endothelin receptor antagonists had no effect on BP, protein excretion, GFR, and kidney morphology in Sprague-Dawley rats without renal cysts. It is concluded that ETA receptor blockade enhances tubular cell proliferation, cyst number, and size and reduces RBF in Han:SPRD rats. This is of major clinical impact because endothelin receptor antagonists are upcoming clinically used drugs.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Histologic Evaluationmentioning

confidence: 99%

Section: Histologic Evaluationmentioning

confidence: 99%

See 1 more Smart Citation

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Hocher¹,

Kalk²,

Slowinski³

et al. 2003

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast to our study, Hocher et al [23] found that in long-term renovascular hypertension in WKY rats, ET A receptor blockade with another compound (BQ-123) completely normalized the hypertrophy of intracardiac arteries compared to untreated 1C-2K, whereas ET B receptor blockade reduced cardiac fibrosis of the left ventricle to baseline values. In another experiment with 1C-2K renovascular hypertensive rats, the same group showed that long-term treatment with the ET A -RB BQ-123 led to a fibrotic atrophy of the clipped kidney characterized by a significantly reduced weight of the clipped kidney compared to the clipped kidney of the placebo-treated group and to a markedly enhanced interstitial fibrosis of these kidneys after long-term ET A blockade [24].…”

Section: Discussionmentioning

confidence: 96%

Effect of Endothelin Blockade on Early Cardiovascular Remodeling in the One-Clip-Two-Kidney Hypertension of the Rat

Saam

Ehmke

Haas³

et al. 2003

Kidney Blood Press Res

View full text Add to dashboard Cite

Background: In models of hypertension and of renal failure, pharmacological blockade of the ET_A receptor has been shown to cause some inconsistent lowering of blood pressure (BP) and lesser left ventricular hypertrophy (LVH). The effects of ET_A receptor blockade (ET_A-RB) on vascular remodeling and their potential relation to BP lowering, have not been clarified. Design: The experimental study in male Sprague-Dawley rats was designed to compare four experimental groups: (1) sham-operated controls (sham); (2) untreated rats with one-clip-two-kidney (1C-2K) renovascular hypertension; (3) 1C-2K rats treated with the ACE inhibitor (ACE-i) trandolapril (0.3 mg/kg b.w./day), and (4) 1C-2K rats treated with the ET_A-RB LU-135252 (50 mg/kg b.w./day). BP was measured weekly by tail plethysmography. After 3 weeks, animals were sacrificed and cardiac, aortic and mesenteric artery morphology was evaluated using morphometric and stereological techniques. Results: Systolic BP was significantly higher in 1C-2K rats compared to sham. BP was not significantly affected by ET_A-RB, but was significantly lowered by the ACE-i. Despite no significant change in BP, ET_A-RB treatment led to a significantly less volume density of the cardiac interstitium (sham 1.40 ± 0.18, 1C-2K 2.66 ± 0.56, 1C-2K + ACE-i 1.88 ± 0.38, 1C-2K + ET_A-RB 2.15 ± 0.37%). In contrast, ET_A-RB had no significant effect on left ventricular/body weight ratio (sham 2.85 ± 0.26, 1C-2K 2.96 ± 0.33, 1C-2K + ACE-i 2.54 ± 0.22 and 1C-2K + ET_A-RB 3.15 ± 0.44 mg/g) or on wall thickness of intramyocardial arteries. Conclusions: The ET_A-RB LU-135252 ameliorated the development of myocardial fibrosis in a short-term hyperreninemic normal salt model of experimental hypertension nearly as effectively as an ACE-i. This effect of LU-135252 is independent of systemic BP. In contrast to findings in other models, ET_A receptor blockade had no significant effect on LVH or vascular remodeling. Only the ACE-i but not the ET_A-RB prevented structural changes of small intramyocardial arteries and of the aorta.

show abstract

“…The essential role of ET B receptors in pathological fibrosis is shown by the observation that an ET B selective receptor antagonist, in contrast to an ET A selective receptor antagonist, prevented the development of cardiac fibrosis in hypertensive rats [Hocher et al, 1999]. ET A selective receptor antagonists actually may enhance renal or cardiac fibrosis [Hocher et al, 2000;Seccia et al, 2003], suggesting that selective ET A antagonism, by causing chronic stimulation of unantagonized ET B receptors, may be detrimental.…”

Section: Cell Proliferation and Fibrosismentioning

confidence: 99%

Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

Clozel¹,

Flores²

2006

Drug Development Research

View full text Add to dashboard Cite

Endothelin has been described as the most potent vasoconstrictor known. Recent research shows that it is also a growth factor, a promoter of fibrosis and inflammation, and a key initiator of endothelial dysfunction. Endothelin becomes, therefore, a candidate in the pathogenesis of many chronic cardiovascular and fibrotic diseases, and inhibition of endothelin function is a potential therapeutic approach for those diseases. Endothelin receptor antagonists are now established therapy in the treatment of pulmonary arterial hypertension, and present promising perspectives in diabetic nephropathy, peripheral arterial disease, hypertension, heart failure, and pulmonary diseases. Endothelin binds to two endothelin receptors, ET A and ET B , and their respective roles are actively debated. A major challenge lies in the understanding of what is the preferred profile for new drugs: selective ET A antagonism or dual ET A and ET B receptor antagonism. A number of cardiovascular diseases are characterized by an up-regulation of smooth muscle cell ET B receptors mediating vasoconstriction and proliferation, and a down-regulation of endothelial ET B receptors, as compared to the physiological state, creating a situation where both ET A and ET B receptors contribute to vasoconstriction and remodeling. When these two receptor subtypes co-exist, a cross-talk between them, probably a result of receptor heterodimerization, suggests that dual ET A /ET B receptor antagonism may be necessary to obtain maximal efficacy. Drug Dev. Res. 67:825-834, 2006.

show abstract

ETA receptor blockade induces fibrosis of the clipped kidney in two-kidney-one-clip renovascular hypertensive rats

Abstract: The present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.

Cited by 34 publications

References 18 publications

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Effect of Endothelin Blockade on Early Cardiovascular Remodeling in the One-Clip-Two-Kidney Hypertension of the Rat

Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

Contact Info

Product

Resources

About