Microcirculation in Renovascular Hypertension Renal artery stenosis (RAS) is becoming a more common etiology of end-stage renal disease. Despite the advances in renal revascularization techniques and stenting, the stenotic kidney often does not improve and even continues to deteriorate after a successful intervention, and the mechanisms leading to these grave outcomes have not been elucidated. We have shown that the kidney after 12 weeks of stenosis has marked microvascular loss and parenchymal damage, accompanied by decreased expression and availability of vascular endothelial growth factor (VEGF), a key physiological and pathological mediator of angiogenesis. Unlike acute ischemia, chronic reduction of renal blood flow (RBF) may fail to sustain VEGF production, which may thereby decrease renal microvascular density and perfusion in the stenotic kidney and lead to progressive and irreversible renal damage. Yet, the role that microvascular damage and loss has in deterioration of the stenotic kidney and the potential for improving the outcomes by protecting the renal microcirculation remain unknown. Importantly, our preliminary data show that RAS increases endothelin (ET)-1, a potent renal vasoconstrictor and down-regulator of the VEGF pathway through activation of the ET-A receptor. Thus, the overall hypothesis underlying this proposal is that RAS results in ET-1 mediated decreases in VEGF, leading to a decreased renal microvascular density, decreased renal function, and irreversible renal injury. Moreover, the current proposal will test the hypothesis that the hemodynamics and function of the stenotic kidney in response to revascularization (by percutaneous trasluminal renal angioplasty) will be improved by preserving the intrarenal microvasculature. We have developed a swine model of RAS that closely mimics the renal functional and structural changes that occur in humans with RAS, allowing us to use powerful physiological imaging techniques to characterize single-kidney function and structure. We have shown that fast computerized tomography (CT) characterizes non-invasively in vivo renal volume, perfusion, GFR, RBF and tubular dynamics, as well as endothelial and epithelial function, while micro-CT allows the 3D reconstruction of the renal microcirculation in situ. Thus, the function and structure of the swine RAS kidneys treated with ET-A receptor blockers or intra-renal VEGF, before and after revascularization, will be studied during the evolution of RAS. Relevance: The role and mechanisms of intra-renal microvascular injury in defining the progression of renal injury and the outcomes of the ischemic kidney after revascularization will be determined for the first time. We will also determine the mechanisms associated with irreversible renal injury, and the timeframe during which the function of the ischemic kidney could be preserved or restored after established renal injury. These studies will advance our understanding of the pathogenesis of renal ischemia, will identify injury markers and predictors of renal viability, and provide viable treatment options for patients with renovascular disease.

Public Health Relevance

Renal artery stenosis, a frequent disease in older adults, produces a narrowing of the diameter of the main renal artery and may cause high blood pressure and renal disease. One approach to fix this condition is to try to open up the blocked renal artery to restore flow of blood to the kidney. However, this procedure is not always effective and some patients still go on to develop kidney disease and high blood pressure, which can lead to heart attacks, strokes, and death. The goal of this research is improve the current therapies used to treat this condition. We believe that by trying to stimulate the growth of additional blood vessels in the kidney that we can improve kidney function in individuals with renal artery stenosis. These studies will greatly advance our understanding of the causes of renal damage resulting from renal artery stenosis, and contribute towards management of patients with this condition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095638-03
Application #
8234092
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Reid, Diane M
Project Start
2010-04-15
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$370,013
Indirect Cost
$122,513
Name
University of Mississippi Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Chade, Alejandro R; Stewart, Nicholas J; Peavy, Patrick R (2014) Disparate effects of single endothelin-A and -B receptor blocker therapy on the progression of renal injury in advanced renovascular disease. Kidney Int 85:833-44
Chade, Alejandro R (2013) Renal vascular structure and rarefaction. Compr Physiol 3:817-31
Stewart, Nicholas; Chade, Alejandro R (2013) Renoprotective effects of hepatocyte growth factor in the stenotic kidney. Am J Physiol Renal Physiol 304:F625-33
Chade, Alejandro R; Stewart, Nicholas (2013) Angiogenic cytokines in renovascular disease: do they have potential for therapeutic use? J Am Soc Hypertens 7:180-90
Flynn, Elizabeth R; Lee, Jonathan; Hutchens Jr, Zachary M et al. (2013) C-peptide preserves the renal microvascular architecture in the streptozotocin-induced diabetic rat. J Diabetes Complications 27:538-47
Chade, Alejandro R; Kelsen, Silvia (2012) Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney: a novel potential therapeutic approach. Am J Physiol Renal Physiol 302:F1342-50
Maric-Bilkan, Christine; Flynn, Elizabeth R; Chade, Alejandro R (2012) Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat. Am J Physiol Renal Physiol 302:F308-15
Stanley, Joanna L; Andersson, Irene J; Hirt, Cassandra J et al. (2012) Effect of the anti-oxidant tempol on fetal growth in a mouse model of fetal growth restriction. Biol Reprod 87:25, 1-8
Chade, Alejandro R (2011) Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis. Am J Physiol Regul Integr Comp Physiol 300:R783-90
Kelsen, Silvia; Hall, John E; Chade, Alejandro R (2011) Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease. Am J Physiol Renal Physiol 301:F218-25

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