Renal Microvascular Rarefaction Research Articles

Super-Resolution Ultrasound Imaging of Renal Vascular Alterations in Zucker Diabetic Fatty Rats during the Development of Diabetic Kidney Disease.

Individuals with diabetes at risk of developing diabetic kidney disease (DKD) are challenging to identify using currently available clinical methods. Prognostic accuracy and initiation of treatment could be improved by a quantification of the renal microvascular rarefaction and the increased vascular tortuosity during the development of DKD. Super-resolution ultrasound (SRUS) imaging is an in vivo technique capable of visualizing blood vessels at sizes below 75 µm. This preclinical study aimed to investigate the alterations in renal blood vessels' density and tortuosity in a type 2 diabetes rat model, Zucker diabetic fatty (ZDF) rats, as a prediction of DKD. Lean age-matched Zucker rats were used as controls. A total of 36 rats were studied, subdivided into ages of 12, 22, and 40 weeks. Measured albuminuria indicated the early stage of DKD, and the SRUS was compared with the ex vivo micro-computed tomography (µCT) of the same kidneys. Assessed using the SRUS imaging, a significantly decreased cortical vascular density was detected in the ZDF rats from 22 weeks of age compared to the healthy controls, concomitant with a significantly increased albuminuria. Already by week 12, a trend towards a decreased cortical vascular density was found prior to the increased albuminuria. The quantified vascular density in µCT corresponded with the in vivo SRUS imaging, presenting a consistently lower vascular density in the ZDF rats. Regarding vessel tortuosity, an overall trend towards an increased tortuosity was present in the ZDF rats. SRUS shows promise for becoming an additional tool for monitoring and prognosing DKD. In the future, large-scale animal studies and human trials are needed for confirmation.

#6465 MIR-451B AND CHRONIC KIDNEY DISEASE: A NOVEL TARGET TO MODULATE RENAL VEGF SIGNALING

Abstract Background and Aims Chronic kidney disease (CKD) is a progressive disorder that affects over 15% of adults worldwide. A major component of CKD pathophysiology is renal microvascular rarefaction and loss that pairs the progression of the disease and complications. We developed a translational swine model of CKD and showed that loss of renal function associates with a significant decrease in renal vascular endothelial growth factor (VEGF) signaling and progressive microvascular (MV) rarefaction. VEGF is a key endogenous cytokine for MV proliferation and repair, but underlying mechanisms of renal VEGF downregulation in CKD are unknown. We hypothesized that micro-RNA (miRNA)-mediated processes contribute to the downregulation of renal VEGF signaling in CKD. Method Unbiased renal micro-RNA (miRNA)-seq was performed in a swine model of CKD stage 3 (14 weeks of bilateral renal artery stenosis + atherogenic diet) and normal controls (n = 5/group). Micro-RNAs up- (>1.4 FC, p<0.05) and down-regulated (<0.7 FC, p<0.05) were identified, followed by target prediction analysis (miRwalk 3.0, Target Scan 7.2). Renal gene and protein expression of VEGF was measured by qPCR and western blot, respectively, and renal MV architecture was studied by 3D micro-CT. Results Unbiased miRNA-seq and target prediction analysis identified four miRs upregulated in the kidney of CKD pigs vs. controls, of which miR-451b (validated by qPCR), broadly conserved among species, was capable of targeting VEGFA (FC = 4.46, p = 0.04). Renal gene and protein expression of VEGF was downregulated in CKD vs. controls, associated with significant cortical and medullary microvascular rarefaction (Figure 1). Conclusion Our data suggest that post-transcriptional modulation of renal VEGF signaling may serve as a prominent mechanism of VEGF downregulation, which leads to MV rarefaction and disease progression in CKD. Furthermore, this work in progress identified a novel candidate (miR-451b) and may set the stage for its targeted modulation to preserve VEGF signaling as a potential strategy to protect the renal microvasculature in CKD.

#3685 PERICYTE AND CXCL12 PLAY CRUCIAL ROLE IN THE RECOVERY OF ACUTE KIDNEY INJURY

Abstract Background and Aims Pericytes are mesenchyme-derived perivascular cells attached to the abluminal surface of capillaries as well as the major origin of myofibroblasts in the animal model of unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI). Although previous studies reported that myofibroblasts may be beneficial during acute kidney injury (AKI) via growth factor secretion, reconstitution and stabilization of the collagen framework for tubular cell regeneration, lack of solid evidence and definite mechanism make the role of pericyte/myofibroblast in AKI remain controversial. Method To clarify this, we used platelet-derived growth factor receptor β (PDGFRβ)-specific antibody following AKI in C57BL/6 mice to inhibit pericytes. In the meantime, We used Gli1-CreERT2;Cxcl12fl/fl genetically modified mice to conditionally knockout CXCL12 specifically in pericytes before IRI. Results The expression of PDGFRβ on pericytes increased after IRI. In group of administration of PDGFRβ antibody, proliferation and transition to myofibroblasts of pericytes were inhibited. Inflammation became worse and renal recovery was impeded after AKI. The chemokine stromal cell-derived factor-1 (SDF-1) which is also known as the C-X-C-type chemokine CXCL12 decreased as well. Furthermore, we demonstrated that CXCL12 was secreted mainly by pericytes and its receptor CXCR4 was expressed on tubular cell during IRI by in situ hybridization. When knockout of CXCL12 was performed before IRI, the renal microvascular rarefaction was noted after AKI and the recovery of renal function was impaired. Renal tubular cell proliferation decreased and apoptosis increased as well. Conclusion In summary, these findings demonstrated that pericytes contribute to renal repair after IRI through CXCL12 secretion.

Imaging the Renal Microcirculation in Cell Therapy.

Renal microvascular rarefaction plays a pivotal role in progressive kidney disease. Therefore, modalities to visualize the microcirculation of the kidney will increase our understanding of disease mechanisms and consequently may provide new approaches for evaluating cell-based therapy. At the moment, however, clinical practice is lacking non-invasive, safe, and efficient imaging modalities to monitor renal microvascular changes over time in patients suffering from renal disease. To emphasize the importance, we summarize current knowledge of the renal microcirculation and discussed the involvement in progressive kidney disease. Moreover, an overview of available imaging techniques to uncover renal microvascular morphology, function, and behavior is presented with the associated benefits and limitations. Ultimately, the necessity to assess and investigate renal disease based on in vivo readouts with a resolution up to capillary level may provide a paradigm shift for diagnosis and therapy in the field of nephrology.

P0117DOSE ESCALATING TOXICOLOGY STUDY OF ELP-VEGF, A NOVEL BIOLOGIC FOR RENAL THERAPEUTIC ANGIOGENESIS

Abstract Background and Aims Chronic renal disease, irrespective of the etiology, is hallmarked by renal microvascular rarefaction. This rarefaction is associated with a reduced bioavailability of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF). Recently, we developed a therapeutic intervention for ischemic renal conditions using therapeutic angiogenesis – supplementing renal VEGF levels. This was achieved by administration of a biopolymer-stabilized form of VEGF using a fusion protein between human VEGF-A121 and an elastin-like polypeptide carrier protein (ELP-VEGF). ELP-VEGF induced microvascular remodeling and increased microvascular density when administered intra-renally in swine models of unilateral renovascular disease (RVD) and chronic kidney disease (CKD), which was associated with improved renal function, reduced renal inflammation, and reduced renal fibrosis. Also, ELP-VEGF targeted the kidney when administered systemically and induced similar beneficial effects on renal function and renal vascular density. The therapeutic dose of ELP-VEGF in the swine models was 0.1 mg/kg when administered intra-renally and 1.0 mg/kg when administered intravenously. The aims of the present study were to determine the maximum tolerated dose of ELP-VEGF and assess its dose-related toxicity. We hypothesize that ELP-VEGF will not exhibit toxicity at therapeutic doses. Method A dose escalating toxicology experiment was performed in Sprague Dawley. Female rats were instrumented with either carotid catheters or carotid artery telemeters for blood pressure monitoring. After a recovery period, a baseline 24-hour urine sample was collected, and baseline glomerular filtration rate (GFR) was measured by monitoring FITC-sinistrin clearance via transdermal fluorescence. A single injection of saline control or ELP-VEGF (0.1, 1, 10, 100, or 200 mg/kg) was administered, and blood pressure was monitored by telemetry or by direct carotid arterial pressure measurements. Body weights were monitored daily throughout the study, and 24-hour urine collections and GFR measurements were repeated 7 and 14 days after protein injection. On day 14 after injection, blood was collected, one kidney was collected and fixed for histological examination, and the second kidney was perfused with Microfil vascular contrast agent for quantification of renal vascular density by micro-CT. Results ELP-VEGF caused no significant changes in body weight at any dose. At the highest doses there was an acute drop in blood pressure (20 – 30 mm Hg at 100 and 200 mg/kg dose, respectively) for approximately twenty minutes post-injection which then normalized. GFR was unchanged by ELP-VEGF at doses up to 100 mg/kg. However, GFR was significantly increased 14 days after treatment with 200 mg/kg ELP-VEGF (1.5 +/- 0.3 versus 2.7 +/- 0.3 mL/min/100 g body weight, p=0.0021). Plasma toxicology revealed no changes in markers of liver or kidney toxicity (AST, ALT, BUN, creatinine, LDH, bilirubin) at any dose or time point. Renal vascular density was unaffected by ELP-VEGF at doses up to 10 mg/kg. However, at 200 mg/kg ELP-VEGF, renal vascular density was significantly decreased for small (0 – 100 micron, p=0.0007) and intermediate (100 – 200 micron, p=0.028) sized vessels Conclusion ELP-VEGF has a proven therapeutic potential for treatment of RVD and CKD at therapeutic doses ranging from 0.1 – 1.0 mg/kg in swine models. Dose escalating toxicity assessment in rats found no effect of ELP-VEGF on body weight, blood pressure, plasma markers of liver and renal toxicity, GFR, or renal vascular density at these therapeutic doses. ELP-VEGF doses of 100 – 200 mg/kg caused transient hypotension immediately after the injection and were associated with increased GFR and loss of renal vascular density, possibly indicating renal damage at ultra-high doses. We conclude that the therapeutic window for ELP-VEGF is 100 – 1,000 times the effective therapeutic dose.

Ultrasound super-resolution imaging provides a noninvasive assessment of renal microvasculature changes during mouse acute kidney injury

Acute kidney injury (AKI) is a risk factor for the development of chronic kidney disease (CKD). One mechanism for this phenomenon is renal microvascular rarefaction and subsequent chronic impairment in perfusion. However, diagnostic tools to monitor the renal microvasculature in a noninvasive and quantitative manner are still lacking. Ultrasound super-resolution imaging is an emerging technology that can identify microvessels with unprecedented resolution. Here, we applied this imaging technique to identify microvessels in the unilateral ischemia-reperfusion injury mouse model of AKI-to-CKD progression invivo. Kidneys from 21 and 42 day post- ischemia-reperfusion injury, the contralateral uninjured kidneys, and kidneys from sham-operated mice were examined by ultrasound super-resolution and histology. Renal microvessels were successfully identified by this imaging modality with a resolution down to 32 μm. Renal fibrosis was observed in all kidneys with ischemia-reperfusion injury and was associated with a significant reduction in kidney size, cortical thickness, relative blood volume, and microvascular density as assessed by this imaging. Tortuosity of the cortical microvasculature was also significantly increased at 42 days compared to sham. These vessel density measurements correlated significantly with CD31 immunohistochemistry (R2=0.77). Thus, ultrasound super-resolution imaging provides unprecedented resolution and is capable of noninvasive quantification of renal vasculature changes associated with AKI-to-CKD progression in mice. Hence, this technique could be a promising diagnostic tool for monitoring progressive kidney disease.

A Boolean Model of Microvascular Rarefaction to Predict Treatment Outcomes in Renal Disease

Despite advances in renovascular disease (RVD) research, gaps remain between experimental and clinical outcomes, translation of results, and the understanding of pathophysiological mechanisms. A predictive tool to indicate support (or lack of) for biological findings may aid clinical translation of therapies. We created a Boolean model of RVD and hypothesized that it would predict outcomes observed in our previous studies using a translational swine model of RVD. Our studies have focused on developing treatments to halt renal microvascular (MV) rarefaction in RVD, a major feature of renal injury. A network topology of 20 factors involved in renal MV rarefaction that allowed simulation of 5 previously tested treatments was created. Each factor was assigned a function based upon its interactions with other variables and assumed to be “on” or “off”. Simulations of interventions were performed until outcomes reached a steady state and analyzed to determine pathological processes that were activated, inactivated, or unchanged vs. RVD with no intervention. Boolean simulations mimicked the results of our previous studies, confirming the importance of MV integrity on treatment outcomes in RVD. Furthermore, our study supports the potential application of a mathematical tool to predict therapeutic feasibility, which may guide the design of future studies for RVD.

Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization.

Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.

SUN-150 RENAL MICROVASCULAR RAREFACTION PRECEDES THE DEVELOPMENT OF HYPERTENSION AND RENAL DAMAGE IN MICE WITH A LOW NEPHRON ENDOWMENT

The a8 integrin chain is a matrix receptor on mesenchymal cells and plays an important role in renal development. a8 integrin-deficient mice (itga8-/-) have a reduced renal mass. Itga8-/- on a C57BL/6 genetic background are normotensive, while itga8-/- on a 129SV background develop hypertension and renal damage. The reduction of renal mass is comparable in both strains. Therefore, hypertension and renal damage are not merely a consequence of low nephron endowment. As hypertension is frequently associated with vascular rarefaction, we studied renal microvascular supply in the kidneys of both itga8-/- strains. Itga8-/- were backcrossed on a C57Bl/6 or on a 129SV background. At the age of 10 and 30 weeks blood pressure was measured by telemetry. At the age of 10 days and 10 weeks the renal microvascular supply was assessed after staining renal tissue with the endothelial cell marker CD31/Pecam. Renal physiological parameters (i.e. albuminuria, serum creatinine and urea) and renal fibrosis (collagen deposition and fibroblast activation) were evaluated. The renal mass of both itga8-/- C57Bl/6 und itga8-/- 129SV was reduced to 50%. Blood pressure was elevated and glomerulosclerosis was detected at the age of 10 weeks in itga8-/- 129SV only. Serum creatinine, serum urea and albuminuria were increased in itga8-/- 129SV, not in itga8-/- C57Bl/6. On the C57Bl/6 background there were no differences in renal capillary numbers of itga8-/- compared to itga8+/+ controls. In contrast, a reduced renal capillary supply was observed in itga8-/- on a 129SV background at the age of 10 weeks. In this strain, a reduced number of renal capillaries was already detected at the age of 10 days, when no overt renal changes could be observed. The development of hypertension in itga8-/- mice with a reduced renal mass is associated with renal microvascular rarefaction. A reduced number of capillaries in the kidney of these mice can be detected as early as at day 10 of life, and might therefore precede the development of hypertension and glomerulosclerosis and contribute to renal damage.

Renal Microvascular Rarefaction Accompanies Interstitial Fibrosis and Tubular Damage in One Kidney‐Deoxycorticosterone Acetate‐Salt (1K/DOCA/salt)‐Dependent Hypertension

High dietary salt intake is a risk factor for hypertension and chronic kidney disease. However, the mechanisms involved remain poorly understood. Microvascular rarefaction ‐ defined as the loss of arterioles and capillaries within a tissue ‐ has the potential to increase total peripheral vascular resistance and cause local hypoxia and tissue damage. Here we utilised one kidney‐deoxycorticosterone acetate‐salt (1K/DOCA/salt)‐treated mice to investigate whether the development of hypertension and renal damage are associated with microvascular rarefaction. C57BL6/J mice were uninephrectomised and treated for 21 d with DOCA (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water. Normotensive controls were uninephrectomized and received a placebo pellet and normal drinking water (1K/placebo). Blood pressure (BP) was measured via tail cuff; renal vascular density was assessed immunohistochemically as the percentage area of CD31‐positive staining; renal collagen was detected with picrosirius red; and hematoxylin and eosin were used to visualise renal inflammation and histopathology. 1K/DOCA/salt‐treated mice had higher BPs (160±4 vs. 126±4 mmHg; n≥7; P≤0.0001) and renal weights (321±16 vs. 251±13 mg; n≥7; P<0.05) than 1K/placebo mice. 1K/DOCA/salt‐treated mice also displayed marked renal fibrosis, inflammation and damage as evidenced by a 10‐fold increase in interstitial collagen (n≥7; P<0.05), the presence of inflammatory cells, tubular dilatation and atrophy, and a loss of epithelial brush borders. Importantly, 1K/DOCA/salt‐treatment was associated with a 50% reduction in microvascular density (n≥7; P<0.05), mainly due to a loss of peritubular capillaries. Correlation analyses revealed a trend for an inverse association of peritubular capillary density with collagen deposition (n≥7; r= −0.7058; P= 0.117), but not with BP or inflammatory cell infiltration. Low magnification analysis of kidney sections revealed that peritubular capillary loss occurred in bands emanating from the arcuate arteries. Moreover, collagen deposition, inflammatory cell infiltration and tubular atrophy displayed a similar banding pattern. In summary, these studies reveal a likely association between microvascular rarefaction and fibrosis during the development of 1K/DOCA/salt‐dependent hypertension and renal damage. Future studies will assess whether strategies aimed at maintaining renal microvascular density can minimise renal fibrosis and damage.Support or Funding InformationThe work was funded by the National Health and Medical Research Council of Australia (GNT1143674)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Contrast-enhanced CT imaging in patients with chronic kidney disease.

Renal microvascular rarefaction characterizes chronic kidney disease (CKD). In murine models of CKD, micro-CT imaging reflected capillary rarefaction using quantification of renal relative blood volume (rBV). In addition, micro-CT imaging revealed morphological alterations of the intrarenal vasculature including reduced vascular branching and lumen diameter. Here, we retrospectively quantified rBV in contrast-enhanced CT angiography in patients and found that, compared to non-CKD patients, those with CKD and renal fibrosis had significantly reduced rBV in the renal cortex. rBV values closely mirrored capillary rarefaction in the corresponding nephrectomy specimens. In patients with follow-up CT angiography, reduction of renal function was paralleled by a decline in rBV. Using virtual autopsy, i.e., postmortem CT angiography, morphometry of intrarenal arteries in 3D-rendered CT images revealed significantly reduced arterial diameter and branching in CKD compared to non-CKD cases. In conclusion, in CKD patients, contrast-enhanced CT imaging with quantification of rBV correlates with functional renal vasculature, whereas virtual autopsy allows morphometric analyses of macrovascular changes. Importantly, the observed vascular alterations in CKD patients mirror those in animals with progressive CKD, suggesting a high relevance of animal models for studying vascular alterations in CKD and renal fibrosis.

Endothelin-a receptor antagonism after renal angioplasty enhances renal recovery in renovascular disease.

Percutaneous transluminal renal angioplasty/stenting (PTRAS) is frequently used to treat renal artery stenosis and renovascular disease (RVD); however, renal function is restored in less than one half of the cases. This study was designed to test a novel intervention that could refine PTRAS and enhance renal recovery in RVD. Renal function was quantified in pigs after 6 weeks of chronic RVD (induced by unilateral renal artery stenosis), established renal damage, and hypertension. Pigs with RVD then underwent PTRAS and were randomized into three groups: placebo (RVD+PTRAS), chronic endothelin-A receptor (ET-A) blockade (RVD+PTRAS+ET-A), and chronic dual ET-A/B blockade (RVD+PTRAS+ET-A/B) for 4 weeks. Renal function was again evaluated after treatments, and then, ex vivo studies were performed on the stented kidney. PTRAS resolved renal stenosis, attenuated hypertension, and improved renal function but did not resolve renal microvascular rarefaction, remodeling, or renal fibrosis. ET-A blocker therapy after PTRAS significantly improved hypertension, microvascular rarefaction, and renal injury and led to greater recovery of renal function. Conversely, combined ET-A/B blockade therapy blunted the therapeutic effects of PTRAS alone or PTRAS followed by ET-A blockade. These data suggest that ET-A receptor blockade therapy could serve as a coadjuvant intervention to enhance the outcomes of PTRAS in RVD. These results also suggest that ET-B receptors are important for renal function in RVD and may contribute to recovery after PTRAS. Using clinically available compounds and techniques, our results could contribute to both refinement and design of new therapeutic strategies in chronic RVD.

Disparate effects of single endothelin-A and -B receptor blocker therapy on the progression of renal injury in advanced renovascular disease

We hypothesized that chronic specific endothelin (ET)-A receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed-tomography. All pigs with renovascular disease were divided such that 7 were untreated, 7 were treated with ET-A blockers, and 5 were treated with ET-B blockers. Four weeks later, all pigs were re-studied in vivo, then euthanized and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. RBF, GFR, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation and fibrosis in the stenotic kidney. These effects were functionally consequential since ET-A blockade improved single kidney microvascular endothelial function, RBF, and GFR, and decreased albuminuria.

Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution regarding antioxidant strategies in RAS.

Microvascular Plasticity and Experimental Heart Failure

Angiogenesis is an essential process in adulthood during wound healing and restoration of blood flow to injured tissues. Angiogenesis is regulated by a very sensitive interplay of growth factors and inhibitors; their imbalance can lead to very diverse diseases. Excessive angiogenesis is involved in malignant, diabetic retinopathy and inflammatory disorders (eg, rheumatoid arthritis, psoriasis, atherosclerosis). Conversely, insufficient angiogenesis may underlie conditions such as ischemic heart diseases, stroke, hypertension, and diabetes. Hence, during the evolution of these degenerative pathologies, inadequate blood vessel growth and insufficient microvascular density leads to poor circulation and tissue suffering or, ultimately, necrosis and death.1 In several physiological conditions, such as muscular exercise training and detraining, acclimatization to altitude, and aging, an adaptation of the microvascular network structure and function to new conditions has been reported.2,3 Interestingly, there is a close link between cerebral angiogenesis and learning; during cognitive decline in relation to senescence or degenerative cerebral diseases, microvascular density is decreased in specific cerebral areas. Specifically, there is a striking relationship between the capillary density, the cerebral tissue blood flow, the local glucose use, and other measures of neuronal signaling, such as the NA+/K+ ATPase (reviewed in Reference 4). Therefore, microvascular plasticity, defined as the ability of the arteriole and capillary network to adapt to the metabolic local conditions by proangiogenesis or antiangiogenesis processes, likely plays a key role in many tissue homeostatic processes. In hypertension, the role of microcirculation (arteriolar and capillary) is of particular importance in increasing periph-eral resistance …