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Angiotensin II type 2 receptor in chronic kidney disease: the good side of angiotensin II?

2009; Elsevier BV; Volume: 75; Issue: 10 Linguagem: Inglês

10.1038/ki.2009.59

1523-1755

Karen A. Griffin, A. Bidani,

Hormonal Regulation and Hypertension

Angiotensin II is believed to mediate blood pressure-independent progressive renal damage in chronic kidney disease (CKD). The evidence is less definitive than has been implied, and the studies by Benndorf et al. suggest that angiotensin II acting through its type 2 receptor may even have beneficial effects, although the responsible mechanisms remain to be defined. These and other data suggest that the concept of blood pressure-independent angiotensin signaling being uniformly deleterious in CKD is an oversimplification that needs re-evaluation. Angiotensin II is believed to mediate blood pressure-independent progressive renal damage in chronic kidney disease (CKD). The evidence is less definitive than has been implied, and the studies by Benndorf et al. suggest that angiotensin II acting through its type 2 receptor may even have beneficial effects, although the responsible mechanisms remain to be defined. These and other data suggest that the concept of blood pressure-independent angiotensin signaling being uniformly deleterious in CKD is an oversimplification that needs re-evaluation. The renin–angiotensin system (RAS) serves a critical homeostatic function in the regulation of body fluid volumes and blood pressure (BP). But in patients with chronic kidney disease (CKD), an inadequately suppressed RAS with associated volume expansion may be largely responsible for the very high prevalence of hypertension and the associated downstream consequences. Nonetheless, in the context of renal disease progression, it is the BP-independent deleterious effects of angiotensin II mediated through angiotensin II type 1 (AT1) receptors that have received the greatest emphasis. Accordingly, current CKD management guidelines emphasize angiotensin-converting enzyme inhibitors or AT1 receptor blockers as specific antiproteinuric and renoprotective therapy independent of their antihypertensive effects. Indeed, RAS blockade at more than one step of the cascade is being recommended by some in the continuing search for ever more complete RAS inhibition. The results of Benndorf et al.1.Benndorf R.A. Krebs C. Hirsch-Hoffmann B. et al.Angiotensin II type 2 receptor deficiency aggravates renal injury and reduces survival in chronic kidney disease in mice.Kidney Int. 2009; 75 (this issue)Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar (this issue) in AT2 receptor-deficient mice add to a small and growing but still-controversial literature that suggests that the biology of downstream angiotensin II signaling in CKD may be more complex and not always predictive of deleterious consequences. Given that the AT2 receptor is generally postulated to antagonize the effects of AT1 receptor activation,2.Siragy H.M. AT1 and AT2 receptor in the kidney: role in health and disease.Semin Nephrol. 2004; 24: 93-100Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar the data of Benndorf et al.1.Benndorf R.A. Krebs C. Hirsch-Hoffmann B. et al.Angiotensin II type 2 receptor deficiency aggravates renal injury and reduces survival in chronic kidney disease in mice.Kidney Int. 2009; 75 (this issue)Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar imply that the greater severity of renal damage observed in AT2–/– mice after 5/6 ablation may be a consequence of either some unantagonized AT1 effect or, alternatively, the loss of an independently beneficial AT2 effect. A plethora of potential AT1 receptor-mediated deleterious mechanisms have been postulated through investigations in a variety of disease models and in vitro systems.1.Benndorf R.A. Krebs C. Hirsch-Hoffmann B. et al.Angiotensin II type 2 receptor deficiency aggravates renal injury and reduces survival in chronic kidney disease in mice.Kidney Int. 2009; 75 (this issue)Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 2.Siragy H.M. AT1 and AT2 receptor in the kidney: role in health and disease.Semin Nephrol. 2004; 24: 93-100Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar These range from increased oxidative stress to an activation of growth factors, cytokines, chemokines, and pre-inflammatory and fibrogenic mediators through G protein-coupled and G protein-independent signaling cascades involving mitogen-activated protein kinases, extracellular signal-regulated kinases, and JAK/STAT pathways. However, pressure (barotrauma) and tissue stress and/or injury per se can also activate many of these downstream pathways.3.Griffin K.A. Bidani A.K. Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade.Clin J Am Soc Nephrol. 2006; 1: 1054-1065Crossref PubMed Scopus (76) Google Scholar Therefore, controversy persists as to the precise contribution of BP-dependent and -independent pathways to the observed tissue damage in the in vivo models, given that the BP-independence has only been established in such studies by isolated tail-cuff BP measurements that are clearly inadequate for this objective.4.Kurtz T.W. Griffin K.A. Bidani A.K. et al.Recommendations for blood pressure measurement in humans and experimental animals. Part 2: Blood pressure measurements in experimental animals: a statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research.Hypertension. 2005; 45: 299-310Crossref PubMed Scopus (224) Google Scholar But the fact that these pathways can also be initiated by angiotensin II in in vitro systems has been cited to support the likely BP-independence of the in vivo effects. However, such inferences may not be valid. Clearly, these deleterious pathways are not activated by a low-salt diet despite large increases in angiotensin II levels. The elegant studies of renal cross-transplantation between AT1−/− and wild-type control mice reported by Crowley et al. also provide a striking and fairly definitive illustration of this inability of angiotensin II per se to trigger adverse signaling pathways in cardiac tissue.5.Crowley S.D. Gurley S.B. Herrera M.J. et al.Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.Proc Natl Acad Sci USA. 2006; 103: 17985-17990Crossref PubMed Scopus (475) Google Scholar While kidney AT1 receptors were found to be required for the hypertensive response to angiotensin II infusion, in the absence of hypertension (wild-type mice with kidneys transplanted from AT1−/− animals), no cardiac hypertrophy or injury was observed despite the presence of AT1 receptors and high concentrations of infused angiotensin II. Conversely, AT1−/− mice with kidneys transplanted from AT1+/+ mice developed hypertension and cardiac hypertrophy and damage comparable to that seen in wild-type mice when exogenous angiotensin was infused, even though cardiac AT1 receptors were lacking. Thus, hypertension is both necessary and sufficient, whereas cardiac AT1 receptors are neither necessary nor sufficient, for cardiac injury after exogenous angiotensin II infusion. Collectively, such data indicate a context-appropriate regulation of AT1 receptor-mediated signaling pathways. Moreover, these results, although contrary to conventional wisdom, are nevertheless entirely consistent with the recent clinical cardiovascular trials that have failed to demonstrate the expected BP-independent superiority of RAS blockade over other antihypertensive classes for cardiovascular end points.6.Chobanian A.V. Bakris G.L. Black H.R. et al.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.JAMA. 2003; 289: 2560-2572Crossref PubMed Scopus (15057) Google Scholar Nevertheless, the potential for BP-independent deleterious effects of angiotensin II might be greater in the kidney because of its capacity for preferential efferent arteriolar constriction. Indeed, this mechanism is postulated to play a major role in the glomerular hypertension observed in the 5/6 renal ablation model. The methodologic limitations of such micropuncture data obtained under anesthesia have been reviewed in detail elsewhere.7.Griffin K.A. Kramer H. Bidani A.K. Adverse renal consequences of obesity.Am J Physiol. 2008; 294: F685-F696Crossref PubMed Scopus (174) Google Scholar Moreover, preferential angiotensin II-mediated vasoconstriction has classically been demonstrated in low-perfusion pressure states associated with reduced macula densa flow (renal artery stenosis, hypovolemia), which stimulate not only renin release but also concurrent cyclooxygenase-2-mediated prostaglandin E2 release from the macula densa. Prostaglandin E2 attenuates afferent but not efferent responses to angiotensin II. This results in selective efferent constriction and a context-appropriate preferential preservation of glomerular filtration rate and glomerular capillary pressure PGC in renal hypoperfusion states8.Loutzenhiser R. Griffin K. Williamson G. Bidani A. Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms.Am J Physiol. 2006; 290: R1153-R1167Crossref PubMed Scopus (193) Google Scholar—hence the sensitivity to nonsteroidal anti-inflammatory drug (NSAID)-induced acute renal failure ARF in such states. It is unlikely that a selective angiotensin II-mediated efferent constriction is a feature of ambient glomerular hemodynamics in the volume-replete normotensive state or the volume-expanded hypertensive CKD models. Moreover, substantial evidence indicates that pathogenic glomerular hypertension in CKD models is primarily a consequence of an impairment of the autoregulatory responses of the dilated afferent arterioles that normally protect the glomerular capillaries from transmission of systemic BP elevations, episodic or sustained.3.Griffin K.A. Bidani A.K. Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade.Clin J Am Soc Nephrol. 2006; 1: 1054-1065Crossref PubMed Scopus (76) Google Scholar This results in a greatly reduced BP threshold for glomerular injury, as current guidelines now recognize.6.Chobanian A.V. Bakris G.L. Black H.R. et al.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.JAMA. 2003; 289: 2560-2572Crossref PubMed Scopus (15057) Google Scholar Consistent with such interpretations, the marked differences seen in the susceptibility to glomerulosclerosis across species and rodent strains after 5/6 ablation largely parallel the differences in their susceptibility to develop hypertension.3.Griffin K.A. Bidani A.K. Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade.Clin J Am Soc Nephrol. 2006; 1: 1054-1065Crossref PubMed Scopus (76) Google Scholar Similarly, no evidence of the BP-independent glomeruloprotection by RAS blockade in the 5/6 ablation model is seen when BP is measured radiotelemetrically as would be expected with angiotensin II-mediated efferent constriction.3.Griffin K.A. Bidani A.K. Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade.Clin J Am Soc Nephrol. 2006; 1: 1054-1065Crossref PubMed Scopus (76) Google Scholar Glomeruloprotection is found to be proportional to the achieved BP reductions with most antihypertensive agents, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but not calcium channel blockers. Unlike other antihypertensives, calcium channel blockers predictably further impair renal autoregulation, lower the BP threshold for glomerulosclerosis, and steepen the slope of the relationship between BP and glomerulosclerosis.3.Griffin K.A. Bidani A.K. Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade.Clin J Am Soc Nephrol. 2006; 1: 1054-1065Crossref PubMed Scopus (76) Google Scholar Accordingly, less glomeruloprotection is achieved for a given BP reduction. These effects are relevant to the interpretations of the clinical trial data showing superior renal outcomes with RAS blockade. Such trials have either used calcium channel blockers in the comparator arms or failed to achieve equal BP lowering.3.Griffin K.A. Bidani A.K. Progression of renal disease: renoprotective specificity of renin-angiotensin system blockade.Clin J Am Soc Nephrol. 2006; 1: 1054-1065Crossref PubMed Scopus (76) Google Scholar Given this background, how might the AT2 receptor deficiency result in increased renal damage in the 5/6 ablation model? On balance, the data suggest a loss of a beneficial effect of AT2 receptor activation after 5/6 ablation (Figure 1). Evidence of AT1 receptor upregulation or a greater severity of hypertension with the use of BP radiotelemetry, as might have been anticipated, was not found. However, despite similar systemic BP, PGC profiles may have differed because of differences in efferent resistance. Given the postulated role of the AT2 receptor in nitric oxide production that may normally exert a tonic vasodilatory effect on the efferent arteriole,2.Siragy H.M. AT1 and AT2 receptor in the kidney: role in health and disease.Semin Nephrol. 2004; 24: 93-100Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar it is possible that in states of marked PGC elevations as after 5/6 ablation, a loss of such AT2 receptor-mediated efferent vasodilation becomes pathogenetically more important. Although endothelial nitric oxide synthase expression was not different, a loss of neuronal nitric oxide synthase (not examined) may potentially be more important in CKD models.9.Baylis C. Nitric oxide deficiency in chronic kidney disease.Am J Physiol. 2008; 294: F1-F9Crossref PubMed Scopus (281) Google Scholar Such a loss, possibly acting through both BP-dependent and BP-independent mechanisms, has been postulated to promote progressive glomerular injury in a variety of models, including the 5/6 ablation model. The increased levels of asymmetric dimethylarginine that were noted, perhaps in part as a result of greater renal function loss in the AT2 receptor-deficient mice, may have further depressed nitric oxide synthesis and contributed to glomerular hypertension and renal damage. Clearly, much work needs to be done, including confirmation of these effects of AT2 receptor deficiency on other genetic backgrounds, before the responsible mechanisms are elucidated and the overall significance of these observations in AT2 receptor-deficient mice is established. Nevertheless, such observations, combined with the data of Crowley et al.5.Crowley S.D. Gurley S.B. Herrera M.J. et al.Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.Proc Natl Acad Sci USA. 2006; 103: 17985-17990Crossref PubMed Scopus (475) Google Scholar and the lack of adverse downstream signaling after a low-salt diet, suggest that current formulations regarding the uniformly deleterious consequences of angiotensin signaling in CKD may be overly simplistic and need re-examination. For instance, even AT1 receptor-mediated BP-independent signaling has the potential for beneficial effects, as suggested by the intriguing observations of Nishida et al. that AT1 receptor deficiency in bone marrow-derived macrophages may promote increased renal fibrosis.10.Nishida M. Fujinaka H. Matsusaka T. et al.Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.J Clin Invest. 2002; 110: 1859-1868Crossref PubMed Scopus (114) Google Scholar Similarly, although severe AT1 receptor-mediated afferent constriction as after high-dose angiotensin II infusions causes ischemia, more modest constriction at physiologic angiotensin II concentrations would in fact be expected to be protective by reducing glomerular BP transmission. Additionally, angiotensin II even at subpressor levels has also been noted to potentiate the myogenic responses to pressure changes, which would also be expected to be protective.11.Kirton C.A. Loutzenhiser R. Alterations in basal protein kinase C activity modulate renal afferent arteriolar myogenic reactivity.Am J Physiol. 1998; 275: H467-H475PubMed Google Scholar The fact that more complete dual RAS blockade with ramipril and telmisartan in the ONTARGET trial not only failed to provide additional benefits as compared with monotherapy but in fact had adverse renal effects,12.Mann J.F. Schmieder R.E. McQueen M. et al.Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomized, double-blind, controlled trial.Lancet. 2008; 372: 547-553Abstract Full Text Full Text PDF PubMed Scopus (1286) Google Scholar only reinforces the need for such a reassessment.