Kidney International (2008) 74 257
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© 2008 International Society of Nephrology
The compromise of renal microvascular structure has received considerable atten- tion as a central and possibly causative feature of the development of chronic fibrotic kidney diseases. The reduction in capillary number has been reported in a number of chronic diseases and has been suggested to promote fibrosis in a variety of different ways, including the exacerbation of hypoxia.1,2 However, in the case of chronic kidney disease, the reduction of renal microvessels repre- sents a chicken-and-egg dilemma: does microvessel dropout contribute to renal fibrosis, or does developing renal fibro- sis impinge on renal capillary stability? The answer to this is not known, but data derived from acute or subtle injury mod- els (folate, ischemia, nephrotoxin, tran- sient angiotensin II) demonstrate a loss of capillaries that typically precedes the development of prominent fibrosis.3–5
These observations suggest that pres- ervation or reversal of microvascular loss in a reversible injury model represents a sound strategy for ameliorating the
Challenges of targeting vascular stability in acute kidney injury David P. Basile1
Acute kidney injury following folate administration is characterized by a vascular remodeling that is initially proliferative but subsequently results in vascular endothelial loss. Interventions directed toward promoting endothelial growth may preserve vascular structure and therefore renal function. However, angiopoietin-1 therapy in the setting of folate-induced acute kidney injury resulted in an expanded fibrotic response despite apparent preservation of the vasculature, indicating that renal repair responses are complex and vascular-directed therapies should be approached with caution. Kidney International (2008) 74, 257–258. doi:10.1038/ki.2008.243
development of renal interstitial fibrosis, as well as addressing the role of vascular dropout as an antecedent event in pro- gressing disease. We and others have dem- onstrated that a number of factors with potential to influence vascular growth are altered in the early course of renal injury (in our experience using ischemia/reper- fusion) and have argued that replacement or enhancement of these factors should maintain blood vessel structure and influ- ence long-term outcome.1,6,7
Angiopoietin-1 is a potent angiogenic factor that interacts with the Tie-2 recep- tor on endothelial cells. Angiopoietin-1 has little or no proliferative potential but is a potent inhibitor of endothelial apop- tosis.8 Angiopoietin-1 has promigratory effects on endothelial cells, and this may relate to its important activity facilitat- ing tube formation during angiogenesis. Angiopoietin-1 stimulation also tightens endothelial junctions to reduce vascular leakiness, and this activity may be related to its anti-inflammatory effects. In general, angiopoietin-1 is considered a prominent vascular stabilizing factor in the develop- ment of new blood vessels. Although the effects of angiopoietin-1 are complicated by the sometimes antagonistic activity of the related protein angiopoietin-2, the activities suggest that angiopoietin-1 is ideally suited as a molecule with potential to preserve blood vessels therapeutically.8
The regenerating kidney after an acute insult provides an opportunity to intervene at a potentially critical window of time in which remodeling events may influence vascular integrity and affect long-term function. Angiopoietin-1 expression is increased in a model of acute kidney injury induced by folate administration9 and recently was also shown to be increased in a model of ischemic acute kidney injury.7 It is reasonable to hypothesize that such alterations in expression may represent an attempt to preserve the renal vascula- ture undergoing active injury. It could be suggested that further enhancement of angiopoietin-1 would enhance vascular preservation following acute injury. As it turns out, it also represents an invitation for unanticipated complications.
Long et al.10 (this issue) have sought to address the potential therapeutic role of angiopoietin-1 using adenoviral delivery of a modified human angiopoietin-1 in a mouse model of folate-induced acute kid- ney injury. This model is typically associ- ated with an early (2–3 days) proliferation of cortical capillary endothelial cells fol- lowed by a gradual regression of these cap- illaries at longer times during recovery.9 It was hypothesized that angiopoietin-1 delivery may prevent the regression of capillaries in this model. This indeed was the case. Interestingly, the investigators also observed the simultaneous enhance- ment of interstitial fibrosis characterized by collagen deposition and increased inflammatory-cell deposition.10
Although the authors may have antici- pated different results, the implications of these findings are profound and impactful among those who are interested in vascu- lar repair processes and their potential to affect kidney function. The study should raise considerable awareness of the com- plicated nature of renal repair character- ized by a complex milieu of cell types and altered chemical signaling. It forces atten- tion to the fact that although angiogenesis may be observed in cultures in response to a given trophic factor, in vivo these molecules are promiscuous and may be highly inflammatory depending on the specific setting. It reminds us that renal injury has a prominent inflammatory
1Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA Correspondence: David P. Basile, Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA. E-mail: dpbasile@iupui.edu
see original article on page 300
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component that cannot be overlooked in the evaluation of potential interventions.
Importantly, angiopoietin-1 did, appar- ently, preserve vascular integrity as would be predicted, but the added inflammatory activity is contradictory to its generally observed anti-inflammatory activity. The reason for this may represent an interesting area of future investigation. However, there is evidence that angiopoietin-1 may activate a cascade of inflammatory cytokines.11
In addition, the results should high- light that therapy geared toward vascular preservation or repair may not be ubiqui- tously applied across pathophysiological conditions. Clearly, as the authors noted,10 there has already been considerable atten- tion paid to the potential utility of vascu- lar endothelial growth factor-A, which is protective to blood vessels and prevents further fibrosis in several, but not all, models investigated.12–14 In the case of angiopoietins, a novel and potent form, termed COMP-angiopoietin-1, has been shown to be effective in limiting fibrosis in a model of ureteral obstruction.15 How- ever, as Long et al. point out,10 factors such as the establishment of an effective dose and the form of angiopoietin-1 adminis- tered may also play an important role in outcome. The point of emphasis is that not all conditions are alike, and several other factors may influence vascular stability in disease models. One molecule is not likely to represent a panacea promoting vascular preservation without complications.
Several other questions are brought to mind in consideration of this area of investigation. The first question is whether therapy that targets the vasculature rep- resents a useful approach at all, and if so, what is the basis for deciding what path- ways should be targeted. Although vessel density is clearly compromised and asso- ciated with hypoxia,1 vascular rarefaction does not occur as the sole and isolated event after injury with the potential to complicate chronic kidney function. Recent studies from our laboratory demonstrated that the manifestation of salt-sensitive hypertension and profound secondary chronic kidney disease was essentially nullified by admin- istration of mycophenolate mofetil after the establishment of vascular injury induced by ischemia/reperfusion in rats.16 We interpret these results to suggest that both hypoxia
occurring secondary to vascular loss and a complexity of infiltrating cells are required for the development of fulminant disease and that any of these may represent useful therapeutic targets.
If, as we believe, targeting the vasculature is important, the choice of molecules to be tested may require more specific informa- tion regarding the nature of vascular drop- out. For example, a more global perspective on the alterations of vasculotrophic fac- tors in specific models is required, and therapies should use combinations of factors to compensate for alterations in the angiogenic milieu of the injured kid- ney. Secondly, and related to the previous point, additional knowledge of the likely mechanism by which endothelial cells are lost would be helpful. Curiously, very little is known of the cellular events that lead to the loss of capillary endothelial cells in the setting of acute injury. Although an obvious hypothesis is that endothelial cells undergo apoptosis, aside from a sepsis model there is little direct evidence to sup- port this contention.
As a final point of consideration, we would like to bring attention to the meth- odology used by Long et al.10 to establish preserved vessel density in response to angiopoietin-1 treatment. These investi- gators used CD31 immunohistochemistry to beautiful ly demonstrate that angiopoietin-1- exposed animals have a preserved or enhanced vasculature. This technique is well established, and we have used this approach in our own work. Nev- ertheless, in light of the interesting, unex- pected, and paradoxical results, perhaps further analysis is warranted. Because ves- sels exist to support the perfusion needs of the organ, the physiological efficacy of these preserved vessels should be evaluated more thoroughly. In addition, given that there exist several populations of CD31- positive circulating cells, including many that also express markers of monocyte or macrophage lineage, it is possible that the deposition of such cells, which may be termed ‘angiogenic macrophages,’17 could result in an enhanced inflammatory state masquerading as an angiogenic response.
Regardless, this interesting study high- lights the promise and limitations of targeting the vasculature. In so doing, it defines important obstacles and allows us
to generate new and testable paradigms to mitigate this perplexing problem. DISCLOSURE The authors declared no competing interests.
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