Regression of Renal Vascular Fibrosis by Endothelin Receptor Antagonism

Boffa, Jean‐Jacques; Tharaux, Pierre‐Louis; Dussaule, Jean–Claude; Chatziantoniou, Christos

doi:10.1161/01.hyp.37.2.490

Cited by 89 publications

(67 citation statements)

References 39 publications

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“…We observed that, despite a successful resolution of the stenosis, a combined ET-A/B blockade strategy after PTRAS did not improve renal function, MV damage, or nephrinuria. On the contrary, our results suggest that ET-A/B blocker therapy significantly diminished the beneficial effects of PTRAS or ET-A receptor blockade on the stented kidney, implying that ET-B receptors are necessary to protect the kidney 28 It is possible that addition of ET-B receptor antagonism after PTRAS might have triggered AKI 29 or exacerbated eventual reperfusion injury 30 that was minimized in this model by single ET-A blockade, suggesting a potential interaction between both receptors in controlling renal damage. 9 Another possibility is that the addition of ET-B blockade exacerbated MV remodeling 31 and thus, intrarenal MV resistance in the poststenotic kidney, which may have also played a role later in the minimal or even negative changes in RBF or GFR 4 weeks after PTRAS.…”

Section: Discussioncontrasting

confidence: 76%

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

Chade¹,

Tullos²,

Stewart³

et al. 2015

Journal of the American Society of Nephrology

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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.

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Section: Discussioncontrasting

confidence: 76%

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

Chade¹,

Tullos²,

Stewart³

et al. 2015

Journal of the American Society of Nephrology

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“…3,17,18 Timely blockade of angiotensin II action (angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor antagonists) can promote reversal of renal lesions and ultimately prevent the progression to ESRD in animal models. 3,19,20 However, renin-angiotensin system blockers do not exhibit the same efficiency in arresting or reversing chronic renal disease progression in humans, making the identification of novel targets for therapy urgent. 21,22 The present study examined whether periostin could be such a target.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Periostin Expression Protects against the Development of Renal Inflammation and Fibrosis

Mael-Ainin

Abed

Conway

et al. 2014

Journal of the American Society of Nephrology

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Increased renal expression of periostin, a protein normally involved in embryonic and dental development, correlates with the decline of renal function in experimental models and patient biopsies. Because periostin has been reported to induce cell differentiation, we investigated whether it is also involved in the development of renal disease and whether blocking its abnormal expression improves renal function and/ or structure. After unilateral ureteral obstruction in wild-type mice, we observed a progressive increase in the expression and synthesis of periostin in the obstructed kidney that associated with the progression of renal lesions. In contrast, mice lacking the periostin gene showed less injury-induced interstitial fibrosis and inflammation and were protected against structural alterations. This protection was associated with a preservation of the renal epithelial phenotype. In vitro, administration of TGF-b to renal epithelial cells increased the expression of periostin several-fold, leading to subsequent loss of the epithelial phenotype. Furthermore, treatment of these cells with periostin increased the expression of collagen I and stimulated the phosphorylation of FAK, p38, and ERK 42/44. In vivo delivery of antisense oligonucleotides to inhibit periostin expression protected animals from L-NAME-induced renal injury. These data strongly suggest that periostin mediates renal disease in response to TGF-b and that blocking periostin may be a promising therapeutic strategy against the development of CKD.

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“…Endothelin receptor antagonism, introduced after the appearance of fibrotic lesions, reduced mortality (Table 1); moreover, the treated animals displayed a less severe degree of glomerular lesions even compared with those at the beginning of the treatment, suggesting thus that renal vascular fibrosis could regress by ET-1 antagonism. 31 However, this regression was partial and less efficient compared to the consequences of angiotensin II antagonism.…”

Section: Mediators Of the Angiotensin II Actionmentioning

confidence: 99%

Reversal of renal disease: is it enough to inhibit the action of angiotensin II?

Chatziantoniou

2007

Cell Death Differ

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Over the last years, evidence emerged demonstrating that the progression of renal fibrosis is reversible in experimental models. The present review summarizes the new insights concerning the mechanisms of progression and regression of renal disease and examines this novel evidence under the light of feasibility and transfer to human nephropathies. The involved mechanisms are discussed with particular emphasis on the fibrotic role of vasoactive peptides such as angiotensin II and endothelin, and growth factors such as transforming growth factor b (TGFb). The possibility of regression is introduced by presenting the in vivo efficiency of anti-hypertensive treatments and of systems that antagonize the fibrogenic action of TGFb such as bone morphogenic protein-7 (BMP-7) and hepatocyte growth factor. Finally, we provide a brief description of the promising future directions and clinical considerations about the applications of the experimental data to humans.

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Regression of Renal Vascular Fibrosis by Endothelin Receptor Antagonism

Cited by 89 publications

References 39 publications

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

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

Inhibition of Periostin Expression Protects against the Development of Renal Inflammation and Fibrosis

Reversal of renal disease: is it enough to inhibit the action of angiotensin II?

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