Chronic kidney disease (CKD) is currently viewed as a generalized vasculopathic state associated with multiple alterations in various vascular beds. Moreover, the kidney can be regarded as an organ, where vascular changes are immediately and sensitively detected by protein (albumin) excretion, already in early stages of vascular disease. The vascular changes have been often considered a consequence of renal disease. However, the fact that several forms of vascular dysfunction occur early in the pathophysiology of CKD has brought the possibility that vascular changes may actually preceed and maybe even determine the progression of renal end-organ damage. This thesis provides data on the role of intrarenal and systemic vascular reactivity in early renal pathology in animal models of experimental and spontaneous renal disease. Chapter 2 introduces the concept, in which microalbuminuria, an early marker of CKD, is associated with both renal and systemic vascular dysfunction. Furthermore, we suggest that therapies targeted to improve early endothelial dysfunction may provide benefit in the primary prevention of CKD and related cardiovascular alterations. Endothelial function predicts the susceptibility to renal end-organ damage. Early vascular changes observed in the individuals with microalbuminuria suggest the role of vascular alterations in the development of CKD. Development of renal damage varies among individuals despite similar levels of blood pressure and it has been proposed that genetic factors might be responsible for increased susceptibility to CKD. Previously, it has been shown that variability in endothelial function among healthy rats of outbred Wistar rat strain predicts the susceptibility of the individual animals to renal injury after 5/6 nephrectomy (5/6Nx). In chapter 3 we demonstrated the predictive property of intrarenal endothelial function in yet another model of experimental renal damage induced by combined unilateral nephrectomy (UnX) and myocardial infarction (MI). We found that individuals with pronounced endothelium-dependent vasodilation of small renal arteries developed lower proteinuria and glomerulosclerosis after UnX+MI. This correlation suggests the presence of an intrarenal vascular factor determining the susceptibility to renal damage induced by cardiac injury. Together with observations from the 5/6 nephrectomy model, it is suggested that hemodynamic alterations mediated by endothelial reactivity may play a role in the development of experimental end-organ damage irrespective of how this damage is inflicted. The present findings implicate that modulation of endothelial function might provide protection against the development of end-organ damage in patients after MI. In chapter 4 we tested the concept of the predictive value of endothelial function in an experimental model with a different etiology of renal damage, i.e., nephropathy induced by the nephrotoxic drug adriamycin. In contrast to previous models, the rats with prominent endothelial relaxation seem to be more prone to the development of renal damage after injection of adriamycin. These contrasting findings suggest that predictive value of renal vascular function is critically dependent on the type of renal injury and etiology of progressive renal damage. However, we additionally found a positive significant correlation between the resulting proteinuria and the level of renal blood flow measured before the induction of injury. This might indicate that in this model, the endothelium-mediated hemodynamic status of the kidney determines the extent of renal damage through regulation of drug delivery to the kidney. Yet, in agreement with hemodynamic models of 5/6Nx and UnX+MI, individuals with pronounced nitric oxide (NO)-mediated vasodilation also seem to be protected against the toxic renal damage, regardless of the total endothelium-mediated vasodilation. Therefore, NO seems to play a protective role in various models of renal injury. Thus, assessment of NO-mediated relaxation may provide more consistent information on the susceptibility to renal end-organ damage than total endothelial response. This is in line with the protective role of NO against renal damage, described by several other authors. Consequently, drugs aiming at increasing renal NO bioavailability might prove effective in prevention of renal end-organ damage, induced either by nephron number reduction, nephrotoxic drug or myocardial infarction. Endothelial and myogenic dysfunction precede end-organ damage in spontaneous renal disease. Spontaneous animal models prone to the development of renal damage provide a valuable tool to define the genetic background for susceptibility to renal injury. In line with the hypothesis of the predictive value of endothelial function for the development of renal damage, in chapter 5 we describe endothelial dysfunction, preceding the development of proteinuria in the Fawn Hooded hypertensive (FHH) rats, a model of spontaneous hypertension-associated renal disease, when compared to FHL rats, a related strain resistant to hypertension and renal impairment. In this case, however, rather than NO, excessive production of cyclooxygenase-derived constrictive prostanoids was responsible for the impaired renal endothelial vasodilation prior to the development of renal injury. This suggests a specific mechanism of vascular alteration, possibly related to minor elevations of systemic blood pressure in this inbred strain. Furthermore, in the same arteries prior to the development of renal damage, we observed impaired myogenic reactivity, an additional vasoactive mechanism probably involved in the altered renal hemodynamics, hyperfiltration and renal injury, as previously described in other models of spontaneous renal disease. Interestingly, both endothelial and VSMC-mediated changes were specific for the renal vasculature and were not observed in systemic resistance or large conduit arteries, arguing against an a priori relationship between renal and systemic vascular dysfunction in CKD. Yet, another endothelial mediator, EDHF, seems to be impaired in the early course of renal disease in small systemic arteries. This suggests that renal injury might be associated with early renal as well as systemic vascular changes. Myogenic response and EDHF are impaired in systemic vasculature in experimental CKD. Whereas renal vascular changes may determine the severity of renal end-organ damage, impaired systemic reactivity might participate in CKD-related complications, such as hypertension. In chapter 5 we found impaired systemic vascular reactivity in a model of spontaneous renal disease prior to the development of end-organ damage. In chapter 6 we explored the systemic vascular reactivity in the experimental model of 5/6 nephrectomy. Two principal local vasomotor mechanisms in small systemic resistance arteries, VSMC-mediated myogenic constriction and endothelium-mediated EDHF-dependent relaxation were concomitantly altered in this setting, arguing against the hypothesis of their mutual inverse relationship. In this case, myogenic reactivity represents rather a beneficial mechanism counteracting elevated peripheral resistance, whereas loss of EDHF might actively participate in the development of CKD-related cardiovascular problems. Importantly, renoprotective therapeutic intervention in the renin-angiotensin system reversed both systemic vascular changes providing a useful therapeutic strategy to prevent CKD-related cardiovascular alterations. Conclusions and future perspectives. The association of endothelial dysfunction with cardiovascular disease has represented one of the major issues of cardiovascular medicine in recent 20 years. Currently, it becomes more and more clear that vascular changes may be involved in earlier stages of chronic disease development and may even determine the susceptibility to organ damage. Based on our results, measurements of endothelial function may provide a useful prognostic tool to identify individuals prone to end-organ impairment. A similar concept has been proposed for endothelial function in cardiac and systemic arteries in predicting cardiovascular outcomes, however, the majority of studies included high risk individual in contrast to our healthy experimental animals. In kidney, our experimental results will have to be confirmed by human studies. Furthermore, a specific test of nitric oxide-mediated vasodilation should be preferred to total endothelium-mediated vasodilation, as the other endothelial mediators may not properly reflect the sensitivity to renal injury. Although it cannot be concluded from our experiments whether the observed variability in endothelial function is genetically determined, several other authors suggest that the decrease expression of nitric oxide synthase (NOS) is associated with susceptibility to renal damage. Moreover, clinical studies showed an association between polymorphisms of endothelial NOS and CKD in various patient populations. Additionally, endothelial function might be a determinant of renoprotective therapeutic response as suggested in chapter 7. Dietary or pharmacologic strategies, such as plant-derived antioxidants or drugs interfering with the renin-angiotensin system, known to interfere with endothelial function, may prove beneficial in primary preventive strategies against CKD and related cardiovascular events. In addition to the endothelium, VSMC-mediated myogenic response may provide a novel therapeutic target for prevention of early hyperfiltration and subsequent renal pathology. Further characterization of the heterogeneous mechanisms underlying arterial reactivity in various vascular beds will help to further define the intricate relation between renal and systemic vasculature and the role of vascular tone regulation in the development of chronic end-organ damage.
|Qualification||Doctor of Philosophy|
|Publication status||Published - 2006|
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