Published online before print October 2, 2006, doi: 10.1161/01.HYP.0000245138.09687.8a
(Hypertension. 2006;48:834.)
© 2006 American Heart Association, Inc.
Editorial Commentaries |
Role of Endothelin Receptors for Renal Protection and Survival in Hypertension
Waiting for Clinical Trials
From the Department of Medicine (M.B.), Internal Medicine I, Medical Policlinic, University Hospital Zürich, Zurich, Switzerland; Molecular Physiology Laboratory (J.J.M., M.A.B.), Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and the Division of Nephrology (M.K.), Department of Internal Medicine, University of Michigan, Ann Arbor.
Correspondence to Matthias Barton, University Hospital Zürich, Department of Medicine, Internal Medicine I, Medical Policlinic, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail barton{at}usz.ch
Hypertension causes mesangial cell growth and glomerulosclerosis and is an important cause of chronic renal failure.1 Urinary loss of proteins is determined by dysfunction of the glomerular filtration barrier for which intact function of visceral glomerular epithelial cells (podocytes) is critical.2,3 Consequently, microalbuminuria and albuminuria have become reliable and early markers of glomerular disease in hypertensive subjects.1,4 In patients, treatment of hypertension with several types of drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers but also calcium antagonists or ß-blockers, delays the development of renal disease,4 and under certain conditions, proteinuria may actually regress.5 Experimental models of hypertensive renal disease show that established proteinuria and glomerulosclerosis may even be reversed by some drugs.6 However, in the majority of these studies, the drugs also had pronounced antihypertensive effects; thus, pressure-lowering effects of the drugs possibly also contributed to glomerular "healing."7
Mimicking activation of the renin–angiotensin–aldosterone system (RAAS) in rats by infusion of angiotensin II results in hypertension and pronounced vascular hypertrophy8,9; renal and vascular endothelin (ET)-1 synthesis also increases, suggesting an interaction between ET and the RAAS.8,9 This link is further strengthened by studies showing that ETA receptor blockade completely normalizes the structural changes in the vasculature induced by angiotensin II, despite only partially reducing blood pressure.9 Even salt-sensitive hypertension induced by angiotensin II seems to depend on the ET system.10
The interaction between these systems has been investigated further using a genetic model of RAAS-dependent hypertension, a transgenic rat model carrying the mouse renin 2 gene.11 This model of renin-dependent hypertension is characterized by malignant hypertension, and untreated animals die prematurely because of myocardial infarction, heart failure, and stroke.11 Previous studies have investigated the effects of ET blockade on hypertension and target organ injury in this model, but the data available have shown inconsistent effects.12–14 To study the interdependency of hypertension and end organ damage clearly, a "next-generation" transgenic rat model of hypertension in which RAAS-dependent hypertension can be turned on and off at the discretion of the researcher has become available recently15 and provides a very powerful and flexible new model that significantly extends the experimental possibilities afforded by the traditional TGR(mRen2) 27 strain. Not only can therapeutic intervention be initiated in the normotensive, rather than the prehypertensive state, but the degree of blood pressure rise can be determined experimentally providing powerful tools for studies relating the RAAS with the ET system.
In a previous prevention study, Vane
ková et al16 have shown that in traditional Ren-2 transgenic rats treated with high-salt diet, pharmacological blockade of either or both ETA and ET B (ETB) or only the ETA receptor improved renal and left ventricular structure, whereas only ETA receptor blockade had antihypertensive effects. In the present issue of Hypertension, this group extends their previous report, presenting results of a study in which treatment was begun after substantial hypertension had already developed, an approach that is much closer to the clinical situation. Untreated animals showed a high mortality, podocyte injury, thickened glomerular basement membranes, and proteinuria but not yet glomerulosclerosis.17 Although there was an initial drop in blood pressure of animals treated with the ETA antagonist, by the end of treatment, there was no difference in the hypertension between different treatment groups. Blood pressure was measured either by the tail-cuff method or under anesthesia, and small effects of the drug on blood pressure might not have been detected. Nevertheless, only selective blockade of the ETA receptor but not of both ETA and ETB receptors (despite having similar effects on blood pressure) had a striking effect on survival and elevated cardiac ET levels and seemed to have normalized glomerular capillary structure and prevented or reversed podocyte injury and proteinuria.17
The findings by Opoensk
et al17 are remarkable for several reasons: (1) this study for the first time demonstrates beneficial effects of ETA blockade with atrasentan on animal survival and podocyte structure in the face of sustained hypertension; (2) the beneficial effects of treatment on podocyte and glomerular capillary structure and proteinuria occur even before the development of glomerulosclerosis, which, in this animal model, only develops at a later stage after prolonged hypertension18; and (3) although in rodents and humans the ETB receptor is the predominant receptor in the kidney, only selective blockade of the ETA receptor was fully effective. Indeed, blockade of both receptors was considerably less effective for animal survival than selective ETA receptor blockade. It seems, therefore, that ET-1 can exert pressure-independent damage via activation of ETA receptors and that activity at ETB is beneficial. Pressure-independent, deleterious effects of ETA receptor activation have been noted in normotensive aged rats where darusentan, another ETA receptor selective antagonist, reverses preexisting proteinuria, podocyte injury, glomerular capillary hypertrophy, and glomerulosclerosis19 and is associated with expressional changes of the cyclin-dependent kinase inhibitor p21WAF1/CIP1.19 Marked improvements of podocyte injury were also seen in other models of hypertension after aldosterone antagonism19–21 but not after treating hypertension only with hydralazine.21 This suggests that the injured podocyte is responsive only to certain types of treatments can promote recovery of the glomerular filtration barrier.22 Because ET-1 (via activation of ETA receptors)19,23 or angiotensin II24 cause disruption of the podocyte filamentous actin cytoskeleton, blockade of these systems may well be beneficial, stimulating podocytes to promote endothelial cell growth25 or regeneration of glomerular capillaries.25,26 In view these observations and the findings now presented by Opoensk et al,17 it now seems likely that inhibition of the pathways controlling podocyte and glomerular capillary structure are reversible and effective even in the presence of sustained hypertension (Figure).
|
The results reported by Opoensk et al17 also point at a clear role for the ETB receptor having an important vascular and renal back-up function as demonstrated previously under salt-sensitive conditions.27,28 It is, therefore, likely that both salt-dependent and ETB receptor–dependent mechanisms were involved in the beneficial effects of ETA receptor blockade. The improvement of survival may also be because of the effects of ETA antagonists functioning as partial angiotensin-converting enzyme inhibitors in the kidney.29 Another interesting aspect of the study by Opoensk et al17 is that the degree of histological podocyte injury reported, rather than the hypertension, paralleled and was correlated with mortality. Despite some limitations of the morphometric techniques used (no determination of filtration slit density nor determination of true harmonic glomular basement membrane thickness) and a disconnection between histological alterations and proteinuria status, these data are consistent with the podocyte being an effective sensor of stress in the entire vascular bed of the animal. This may be of strong clinical relevance, because urinary excretion of podocytes or podocyte membranes is a highly sensitive marker for renal injury,30,31 and microalbuminuria as the first sign of glomerular filtration barrier failure is a strong predictor of cardiovascular mortality in humans.32 Possibly, improvements in glomerular basement membrane structure seen after ET blockade in hypertensive17 and normotensive19 animals also contribute to the reduction in proteinuria even before podocyte injury occurs.33 This would also explain the dissociation between the degree of podocyte injury and proteinuria status reported by Opoensk et al.17
To test the therapeutic potential of ET antagonists for hypertension and renal disease in patients, clinical studies are needed. A first study initiated by Speedel pharmaceuticals using their newly developed ETA receptor antagonist avosentan (SPP301) added to standard therapy showed pronounced antiproteinuric effects in diabetic subjects with a reduction of proteinuria of >40% after 12 weeks,34 and a phase III trial, the randomized, placebo-controlled Avosentan on Doubling of Serum Creatinine End Stage Renal Disease and Death in Diabetic Nephropathy Trial (ASCEND Trial), is now underway to test the therapeutic efficacy in a larger population of diabetics with diabetic renal failure who often also require antihypertensive therapy.35 Myogen Inc most recently announced the initiation of a phase III trial using the ETA antagonist darusentan (LU135252) in patients with "resistant" hypertension.36 Hypertension resistant to conventional antihypertensive treatment in humans is frequently associated with salt sensitivity for which, at least experimentally, darusentan has been shown to provide substantial organ protection.37,38 In the Fixed Doses of Darusentan as Compared With Placebo in Resistant Hypertension Trial (DORADO Trial), darusentan will be given to patients in whom goal blood pressure though an appropriate 3-drug maximum dose regimen could not be achieved and who are likely to also have hypertensive renal injury. Hopefully, these clinical studies will provide answers to the questions of whether ETA receptor antagonists can provide similar therapeutic benefits to humans as in experimental studies and whether such benefits might translate into an improvement of morbidity and mortality in patients with hypertension and renal disease.
 |
Acknowledgments |
|---|
Sources of Funding
This work was supported by the Swiss National Foundation (SNF 3200-058426.99, 3232-058421.99, and 3200-108258/1) and the Wellcome Trust.
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Remuzzi G, Chiurchiu C, Ruggenenti P. Proteinuria predicting outcome in renal disease: nondiabetic nephropathies (REIN). Kidney Int. 2004; 66 (suppl): S90–S96.[CrossRef]
2. Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003; 83: 253–307.
3. Shankland SJ. The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006; 69: 2131–2147.[CrossRef][Medline] [Order article via Infotrieve]
4. Khan NA, McAlister FA, Rabkin SW, Padwal R, Feldman RD, Campbell NR, Leiter LA, Lewanczuk RZ, Schiffrin EL, Hill MD, Arnold M, Moe G, Campbell TS, Herbert C, Milot A, Stone JA, Burgess E, Hemmelgarn B, Jones C, Larochelle P, Ogilvie RI, Houlden R, Herman RJ, Hamet P, Fodor G, Carruthers G, Culleton B, Dechamplain J, Pylypchuk G, Logan AG, Gledhill N, Petrella R, Tobe S, Touyz RM, Canadian Hypertension Education Program. The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part II- therapy. Can J Cardiol. 2006; 22: 583–593.[Medline] [Order article via Infotrieve]
5. Deferrari G, Ravera M, Deferrari L, Vettoretti S, Ratto E, Parodi D. Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II receptor blockers. J Am Soc Nephrol. 2002; 13 (suppl 3): S224–S229.
6. Fogo AB. Progression versus regression of chronic kidney disease. Nephrol Dial Transplant. 2006; 21: 281–284.
7. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest. 2006; 116: 288–296.[CrossRef][Medline] [Order article via Infotrieve]
8. Barton M, Shaw S, d’Uscio LV, Moreau P, Luscher TF. Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation. Biochem Biophys Res Commun. 1997; 238: 861–865.[CrossRef][Medline] [Order article via Infotrieve]
9. Moreau P, d’Uscio LV, Shaw S, Takase H, Barton M, Luscher TF. Angiotensin II increases tissue endothelin and induces vascular hypertrophy: Reversal by ET(A)-receptor antagonist. Circulation. 1997; 96: 1593–1597.
10. Ballew JR, Fink GD. Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake. Am J Physiol Heart Circ Physiol. 2001; 281: H2218–H2225.
11. Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature (Lond). 1990; 344: 541–544.[CrossRef][Medline] [Order article via Infotrieve]
12. Whitworth CE, Veniant MM, Firth JD, Cumming AD, Mullins JJ. Endothelin in the kidney in malignant phase hypertension. Hypertension. 1995; 26: 925–931.
13. Rossi GP, Sacchetto A, Rizzoni D, Bova S, Porteri E, Mazzocchi G, Belloni AS, Bahcelioglu M, Nussdorfer GG, Pessina AC. Blockade of angiotensin II type 1 receptor and not of endothelin receptor prevents hypertension and cardiovascular disease in transgenic (mREN2)27 rats via adrenocortical steroid-independent mechanisms. Arterioscler Thromb Vasc Biol. 2000; 20: 949–956.
14. Rothermund L, Pinto YM, Hocher B, Vetter R, Leggewie S, Kobetamehl P, Orzechowski HD, Kreutz R, Paul M. Cardiac endothelin system impairs left ventricular function in renin-dependent hypertension via decreased sarcoplasmic reticulum Ca(2+) uptake. Circulation. 2000; 102: 1582–1588.
15. Kantachuvesiri S, Fleming S, Peters J, Peters B, Brooker G, Lammie AG, McGrath I, Kotelevtsev Y, Mullins JJ. Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem. 2001; 276: 36727–36733.
16. Vaneckova I, Kramer HJ, Bäcker A, Vernerová Z, Opoensk M, Cervenka L. Early endothelin-A receptor blockade decreases blood pressure and ameliorates end-organ damage in homozygous Ren-2 rats. Hypertension. 2005; 46: 969–974.
17. Opoensk M, Kramer HJ, Bäcker A, Vernerová Z, Eis V, 
ervenka L, ertíková Chábová V, Tesa
V, Van
ková I. Late-onset endothelin-A receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension. 2006; 48: 965–971.
18. Bachmann S, Peters J, Engler E, Ganten D, Mullins J. Transgenic rats carrying the mouse renin gene–morphological characterization of a low-renin hypertension model. Kidney Int. 1992; 41: 24–36.[Medline] [Order article via Infotrieve]
19. Ortmann J, Amann K, Brandes RP, Kretzler M, Munter K, Parekh N, Traupe T, Lange M, Lattmann T, Barton M. Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension. 2004; 44: 974–981.
20. Nagase M, Shibata S, Yoshida S, Nagase T, Gotoda T, Fujita T. Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker. Hypertension. 2006; 47: 1084–1093.
21. Aldigier JC, Kanjanbuch T, Ma LJ, Brown NJ, Fogo AB. Regression of existing glomerulosclerosis by inhibition of aldosterone. J Am Soc Nephrol. 2005; 16: 3306–3314.
22. Kretzler M. Role of podocytes in focal sclerosis: defining the point of no return. J Am Soc Nephrol. 2005; 16: 2830–2832.
23. Morigi M, Buelli S, Angioletti S, Zanchi C, Longaretti L, Zoja C, Galbusera M, Gastoldi S, Mundel P, Remuzzi G, Benigni A. In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am J Pathol. 2005; 166: 1309–1320.
24. Macconi D, Abbate M, Morigi M, Angioletti S, Mister M, Buelli S, Bonomelli M, Mundel P, Endlich K, Remuzzi A, Remuzzi G. Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target for renoprotective intervention. Am J Pathol. 2006; 168: 1073–1085.
25. Liang XB, Ma LJ, Naito T, Wang Y, Madaio M, Zent R, Pozzi A, Fogo AB. Angiotensin type 1 receptor blocker restores podocyte potential to promote glomerular endothelial cell growth. J Am Soc Nephrol. 2006; 17: 1886–1895.
26. Fogo AB. New capillary growth: a contributor to regression of sclerosis? Curr Opin Nephrol Hypertens. 2005; 14: 201–203.[Medline] [Order article via Infotrieve]
27. Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M. Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J Clin Invest. 2000; 105: 925–933.[Medline] [Order article via Infotrieve]
28. Tazawa N, Okada Y, Nakata M, Izumoto H, Takasu M, Takaoka M, Gariepy CE, Yanagisawa M, Matsumura Y. Exaggerated vascular and renal pathology in endothelin-B-receptor-deficient rats with subtotal nephrectomy. J Cardiovasc Pharmacol. 2004; 44: S467–S470.[CrossRef][Medline] [Order article via Infotrieve]
29. Barton M, Carmona R, Krieger JE, Goettsch W, Morawietz H, d’Uscio LV, Lattmann T, Luscher TF, Shaw S. Endothelin regulates angiotensin-converting enzyme in the mouse kidney. J Cardiovasc Pharmacol. 2000; 36: S244–S247.[Medline] [Order article via Infotrieve]
30. Hara M, Yanagihara T, Kihara I, Higashi K, Fujimoto K, Kajita T. Apical cell membranes are shed into urine from injured podocytes: a novel phenomenon of podocyte injury. J Am Soc Nephrol. 2005; 16: 408–416.
31. Yu D, Petermann A, Kunter U, Rong S, Shankland SJ, Floege J. Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria. J Am Soc Nephrol. 2005; 16: 1733–1741.
32. de Zeeuw D, Parving HH, Henning RH. Microalbuminuria as an early marker for cardiovascular disease. J Am Soc Nephrol. 2006; 17: 2100–2105.
33. Jarad G, Cunningham J, Shaw AS, Miner JH. Proteinuria precedes podocyte abnormalities inLamb2 mice, implicating the glomerular basement membrane as an albumin barrier. J Clin Invest. 2006; 116: 2272–2279.[CrossRef][Medline] [Order article via Infotrieve]
34. Wenzel RR, Mann J, Jürgens C, Yildirim I, Bruck H, Philipp T, Mitchell A. The ETA-selective antagonist SPP301 on top of standard treatment reduces urinary albumin excretion rate in patients with diabetic nephropathy. ASN Renal Week. 2005; F-FC093:Abstract.
35. Speedel. Speedel starts phase III study of SPP301 in diabetic nephropathy. 2005. Available at: http://www.speedel.com/section/7/subsections/4?&form_link=1120715251. Accessed July 19, 2006.
36. Myogen. Myogen initiates phase 3 clinical trial of darusentan in patients with resistant hypertension. 2006. Available at: http://www.myogen.com. Accessed July 13, 2006.
37. Barton M, d’Uscio LV, Shaw S, Meyer P, Moreau P, Luscher TF. ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998; 31: 499–504.
38. Barton M, Vos I, Shaw S, Boer P, D’Uscio LV, Grone HJ, Rabelink TJ, Lattmann T, Moreau P, Luscher TF. Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis. J Am Soc Nephrol. 2000; 11: 835–845.
Related Article:
Hypertension 2006 48: 965-971.
This article has been cited by other articles:
 |
|
 |
|
  M. Barton and M. R. Meyer Postmenopausal Hypertension: Mechanisms and Therapy Hypertension, July 1, 2009; 54(1): 11 - 18. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||