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1.
Am J Nephrol ; 52(3): 228-238, 2021.
Article in English | MEDLINE | ID: mdl-33823527

ABSTRACT

INTRODUCTION: Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. METHODS: We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. RESULTS: We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-ß1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. CONCLUSION: LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.


Subject(s)
Cytokines/physiology , Glycoproteins/physiology , Kidney Diseases/etiology , Kidney/pathology , Microvascular Rarefaction/etiology , Adult , Animals , Female , Fibrosis/etiology , Humans , Male , Mice , Middle Aged
2.
J Clin Endocrinol Metab ; 106(4): 1150-1162, 2021 03 25.
Article in English | MEDLINE | ID: mdl-33367811

ABSTRACT

AIMS: The association of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) has been under-studied and remains unclear. We investigated this relationship using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Veteran Affairs Diabetes Trial (VADT). METHODS: In ACCORD, fasting plasma glucose (FPG) was measured 1 to 3 times/year for up to 84 months in 10 251 individuals. In the VADT, FPG was measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose. The primary composite outcome was time to either severe nephropathy or retinopathy event and secondary outcomes included each outcome individually. To assess the association, we considered variability measures as time-dependent covariates in Cox proportional hazard models. We conducted a meta-analysis across the 2 trials to estimate the risk of fasting glucose variability as well as to assess the heterogenous effects of FPG variability across treatment arms. RESULTS: In both ACCORD and the VADT, the CV and ARV of FPG were associated with development of future microvascular outcomes even after adjusting for other risk factors, including measures of average glycemic control (ie, cumulative average of HbA1c). Meta-analyses of these 2 trials confirmed these findings and indicated FPG variation may be more harmful in those with less intensive glucose control. CONCLUSIONS: This post hoc analysis indicates that variability of FPG plays a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/diagnosis , Diabetic Angiopathies/diagnosis , Adult , Aged , Cohort Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/therapy , Diabetic Angiopathies/blood , Diabetic Angiopathies/etiology , Diabetic Angiopathies/prevention & control , Fasting/blood , Female , Glycemic Control/methods , Heart Disease Risk Factors , Humans , Male , Microvascular Rarefaction/blood , Microvascular Rarefaction/diagnosis , Microvascular Rarefaction/etiology , Middle Aged , Prognosis , Randomized Controlled Trials as Topic , Treatment Outcome , United States , Veterans
3.
Am J Physiol Renal Physiol ; 317(5): F1383-F1397, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31509009

ABSTRACT

Acute kidney injury (AKI) is a strong independent predictor of mortality and often results in incomplete recovery of renal function, leading to progressive chronic kidney disease (CKD). Many clinical trials have been conducted on the basis of promising preclinical data, but no therapeutic interventions have been shown to improve long-term outcomes after AKI. This is partly due to the failure of preclinical studies to accurately model clinically relevant injury and long-term outcomes on CKD progression. Here, we evaluated the long-term effects of AKI on CKD progression in three animal models reflecting diverse etiologies of AKI: repeat-dose cisplatin, rhabdomyolysis, and ischemia-reperfusion injury. Using transdermal measurement of glomerular filtration rate as a clinically relevant measure of kidney function and quantification of peritubular capillary density to measure capillary rarefaction, we showed that repeat-dose cisplatin caused capillary rarefaction and decreased renal function in mice without a significant increase in interstitial fibrosis, whereas rhabdomyolysis-induced AKI led to severe interstitial fibrosis, but renal function and peritubular capillary density were preserved. Furthermore, long-term experiments in mice with unilateral ischemia-reperfusion injury showed that restoration of renal function 12 wk after a contralateral nephrectomy was associated with increasing fibrosis, but a reversal of capillary rarefaction was seen at 4 wk. These data demonstrate that clear dissociation between kidney function and fibrosis in these models of AKI to CKD progression and suggest that peritubular capillary rarefaction is more strongly associated with CKD progression than renal fibrosis.


Subject(s)
Acute Kidney Injury/etiology , Cisplatin/toxicity , Microvascular Rarefaction/pathology , Renal Insufficiency, Chronic/pathology , Reperfusion Injury/complications , Rhabdomyolysis/complications , Animals , Antineoplastic Agents/toxicity , Fibrosis/etiology , Kidney/drug effects , Kidney/pathology , Male , Mice , Microvascular Rarefaction/etiology
4.
Sci Rep ; 9(1): 5909, 2019 04 11.
Article in English | MEDLINE | ID: mdl-30976042

ABSTRACT

The implantation of continuous - flow ventricular assist devices (VAD) is suggested to evoke angiodysplasia contributing to adverse events such as gastrointestinal bleeding. We evaluated in vivo capillary density and glycocalyx dimensions to investigate possible systemic microvascular changes in patients with chronic heart failure and VAD support vs. standard medical treatment. Forty-two patients with VAD support were compared to forty-one patients with ischemic and non-ischemic chronic heart failure (CHF) on standard pharmacotherapy and to a group of forty-two healthy subjects in a prospective cross-sectional study. Sublingual microcirculation was visualized using Sidestream Darkfield videomicroscopy and functional and perfused total capillary densities were quantified. Patients with VAD implantation were followed for one year and bleeding events were recorded. Median time after VAD implantation was 18 months. Patients were treated with centrifugal-flow devices (n = 31) or axial-flow devices (n = 11). Median functional capillary density was significantly lower in patients with VAD therapy as compared to CHF patients (196 vs. 255/mm2, p = 0.042, adjusted p-value). Functional and total capillary densities were 44% and 53% lower (both p < 0.001) in patients with VAD therapy when compared to healthy subjects. Cox regression analysis revealed loss of capillary density as a significant predictor of bleeding events during one -year follow-up of VAD patients (HR: 0.987, CI (95%): 0.977-0.998, p = 0.021 for functional and 0.992, CI (95%): 0.985-0.999, p = 0.03 for total capillary density). In conclusion, patients with VAD support exhibit capillary density rarefaction, which was associated with bleeding events. If confirmed independently, capillary impairment may be evaluated as novel marker of bleeding risk.


Subject(s)
Capillaries/pathology , Cardiomyopathies/therapy , Heart Failure/therapy , Heart-Assist Devices/adverse effects , Microvascular Rarefaction/etiology , Myocardial Ischemia/therapy , Aged , Cardiomyopathies/pathology , Case-Control Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Heart Failure/pathology , Humans , Male , Microcirculation , Microvascular Rarefaction/pathology , Middle Aged , Myocardial Ischemia/pathology , Prognosis , Retrospective Studies
5.
J Transl Med ; 17(1): 91, 2019 03 18.
Article in English | MEDLINE | ID: mdl-30885241

ABSTRACT

BACKGROUND: Hyperoxia-induced bronchopulmonary dysplasia (BPD) models are essential for better understanding and impacting on long-term pulmonary, cardiovascular, and neurological sequelae of this chronic disease. Only few experimental studies have systematically compared structural alterations with lung function measurements. METHODS: In three separate and consecutive series, Sprague-Dawley infant rats were exposed from day of life (DOL) 1 to 19 to either room air (0.21; controls) or to fractions of inspired oxygen (FiO2) of 0.6, 0.8, and 1.0. Our primary outcome parameters were histopathologic analyses of heart, lungs, and respiratory system mechanics, assessed via image analysis tools and the forced oscillation technique, respectively. RESULTS: Exposure to FiO2 of 0.8 and 1.0 resulted in significantly lower body weights and elevated coefficients of lung tissue damping (G) and elastance (H) when compared with controls. Hysteresivity (η) was lower due to a more pronounced increase of H when compared with G. A positive structure-function relation was demonstrated between H and the lung parenchymal content of α-smooth muscle actin (α-SMA) under hyperoxic conditions. Moreover, histology and morphometric analyses revealed alveolar simplification, fewer pulmonary arterioles, increased α-SMA content in pulmonary vessels, and right heart hypertrophy following hyperoxia. Also, in comparison to controls, hyperoxia resulted in significantly lower plasma levels of vascular endothelial growth factor (VEGF). Lastly, rats in hyperoxia showed hyperactive and a more explorative behaviour. CONCLUSIONS: Our in vivo infant rat model mimics clinical key features of BPD. To the best of our knowledge, this is the first BPD rat model demonstrating an association between lung structure and function. Moreover, we provide additional evidence that infant rats subjected to hyperoxia develop rarefaction of pulmonary vessels, augmented vascular α-SMA, and adaptive cardiac hypertrophy. Thus, our model provides a clinically relevant tool to further investigate diseases related to O2 toxicity and to evaluate novel pharmacological treatment strategies.


Subject(s)
Cardiomegaly/etiology , Cardiomegaly/physiopathology , Hyperoxia/complications , Hyperoxia/physiopathology , Lung/pathology , Lung/physiopathology , Microvascular Rarefaction/etiology , Microvascular Rarefaction/physiopathology , Animals , Animals, Newborn , Behavior, Animal , Biomarkers/metabolism , Cardiomegaly/blood , Endothelin-1/blood , Female , Humans , Hyperoxia/blood , Lung/blood supply , Microvascular Rarefaction/blood , Myocardium/pathology , Rats, Sprague-Dawley , Respiratory Mechanics , Social Behavior , Survival Analysis , Vascular Endothelial Growth Factor A/blood , Weight Gain
6.
Mol Med Rep ; 19(4): 3168-3178, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30816496

ABSTRACT

Loss of peritubular capillaries is a notable feature of progressive renal interstitial fibrosis. Astaxanthin (ASX) is a natural carotenoid with various biological activities. The present study aimed to evaluate the effect of ASX on unilateral ureteral obstruction (UUO)­induced renal fibrosis in mice. For that purpose, mice were randomly divided into five treatment groups: Sham, ASX 100 mg/kg, UUO, UUO + ASX 50 mg/kg and UUO + ASX 100 mg/kg. ASX was administered to the mice for 7 or 14 days following UUO. The results demonstrated that UUO­induced histopathological changes in the kidney tissue were prevented by ASX. Renal function was improved by ASX treatment, as evidenced by decreased blood urea nitrogen and serum creatinine levels. Furthermore, the extent of renal fibrosis and collagen deposition induced by UUO was suppressed by ASX. The levels of collagen I, fibronectin and α­smooth muscle actin were increased by UUO in mice or by transforming growth factor (TGF)­ß1 treatment in NRK­52E cells, and were reduced by ASX administration. In addition, ASX inhibited the UUO­induced decrease in peritubular capillary density by upregulating vascular endothelial growth factor and downregulating thrombospondin 1 levels. Inactivation of the TGF­ß1/Smad signaling pathway was involved in the anti­fibrotic mechanism of ASX in UUO mice and TGF­ß1­treated NRK­52E cells. In conclusion, ASX attenuated renal interstitial fibrosis and peritubular capillary rarefaction via inactivation of the TGF­ß1/Smad signaling pathway.


Subject(s)
Fibrinolytic Agents/pharmacology , Kidney Diseases/etiology , Kidney Diseases/pathology , Microvascular Rarefaction/etiology , Microvascular Rarefaction/pathology , Ureteral Obstruction/complications , Animals , Biomarkers , Biopsy , Cell Line , Disease Models, Animal , Fibrosis , Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Male , Mice , Microvascular Rarefaction/drug therapy , Microvascular Rarefaction/metabolism , Rats , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta1/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Xanthophylls/pharmacology
7.
J Mol Histol ; 49(2): 219-228, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29442209

ABSTRACT

Proper and timely assembly of the kidney vasculature with their respective nephrons is crucial during normal kidney development. In this study, we investigated the effects of enalapril (angiotensin-converting enzyme inhibitor) on angiogenesis-related gene expression and microvascular endothelium related to glomeular and tubular changes in the neonatal rat kidney. Enalapril-treated rats had higher tubular injury scores and lower glomerular maturity grades than those of untreated rats. In the enalapril-treated group, intrarenal angiopoietin-2, Tie-2, and thrombospondin-1 protein expression increased, whereas intrarenal angiopoietin-1 protein expression decreased. JG12-positive glomerular and peritubular capillary staining was reduced in the enalapril-treated rat kidney. The number of JG12-positive capillary endothelial cells was directly correlated with glomerular maturation grade and was inversely related with the tubular injury. Our findings suggest the imbalance between pro- and anti-angiogenic factors may be implicated in the loss of capillaries in associated with impaired nephrogenesis after angiotensin II blockade in the developing rat kidney.


Subject(s)
Kidney/blood supply , Microvascular Rarefaction , Angiogenesis Modulating Agents/pharmacology , Angiotensin II/drug effects , Angiotensin-Converting Enzyme Inhibitors , Animals , Animals, Newborn , Enalapril/pharmacology , Kidney/growth & development , Microvascular Rarefaction/etiology , Rats
8.
Cardiology ; 141(4): 202-211, 2018.
Article in English | MEDLINE | ID: mdl-30820009

ABSTRACT

BACKGROUND: Hypertrophic obstructive cardiomyopathy (HOCM) is a myocardial disease characterized by fibrosis and microvascular ischemia. Microvessels play a critical role in myocardial fibrosis in HOCM. However, it remains unclear whether or not myocardial fibrosis is associated with microvascular density (MVD) changes. OBJECTIVE: The aim of the present study was to investigate whether a reduction in MVD is related to myocardial fibrosis in HOCM cardiac samples. METHODS: We analyzed MVD and fibrosis in myectomy left ventricular (LV) septal wall specimens from 53 HOCM patients. Control myocardium from the LV septal wall was collected at autopsy of 9 individuals who died of noncardiac causes. RESULTS: The fibrosis ratio (% area) in HOCM was higher and the MVD was lower than that in control subjects (i.e., 12.7 ± 10.0 vs. 4.0 ± 1.4%, p = 0.012, and 480.9 ± 206.7 vs. 1,425 ± 221/mm2, p < 0.001). Patients with mild fibrosis had a higher MVD than patients with moderate fibrosis (i.e., 568.2 ± 214.8 vs. 403.2 ± 167.8/mm2, p = 0.006) and patients with severe fibrosis (i.e., 568.2 ± 214.8 vs. 378.6 ± 154.0/mm2, p = 0.024). Furthermore, a significant negative correlation was found between myocardial fibrosis and MVD in HOCM patients (r = -0.40, p = 0.003), which was also found in mild fibrosis (r = -0.40, p = 0.043), moderate fibrosis (r = -0.50, p = 0.024), and severe fibrosis (r = -0.24, p = 0.61), although no significant differences were observed in severe fibrosis. Additionally, we demonstrated that late gadolinium enhancement was negatively correlated with MVD (r = -0.37, p = 0.03) and positively correlated with fibrosis (r = 0.44, p = 0.01). CONCLUSION: HOCM patients had a higher myocardial fibrosis ratio and a lower MVD. The severity of myocardial fibrosis was negatively correlated with MVD in HOCM. These findings showed that a reduced MVD may contribute to myocardial fibrosis in HOCM.


Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Heart Septum/diagnostic imaging , Magnetic Resonance Imaging, Cine , Microvascular Rarefaction/diagnostic imaging , Myocardium/pathology , Adult , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/pathology , Contrast Media , Echocardiography , Female , Fibrosis , Gadolinium DTPA , Heart Septum/pathology , Humans , Male , Microvascular Rarefaction/etiology , Microvascular Rarefaction/pathology , Middle Aged , Myocardial Contraction
9.
Age (Dordr) ; 38(4): 273-289, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27613724

ABSTRACT

Strong epidemiological and experimental evidence indicate that both age and hypertension lead to significant functional and structural impairment of the cerebral microcirculation, predisposing to the development of vascular cognitive impairment (VCI) and Alzheimer's disease. Preclinical studies establish a causal link between cognitive decline and microvascular rarefaction in the hippocampus, an area of brain important for learning and memory. Age-related decline in circulating IGF-1 levels results in functional impairment of the cerebral microvessels; however, the mechanistic role of IGF-1 deficiency in impaired hippocampal microvascularization remains elusive. The present study was designed to characterize the additive/synergistic effects of IGF-1 deficiency and hypertension on microvascular density and expression of genes involved in angiogenesis and microvascular regression in the hippocampus. To achieve that goal, we induced hypertension in control and IGF-1 deficient mice (Igf1 f/f  + TBG-Cre-AAV8) by chronic infusion of angiotensin II. We found that circulating IGF-1 deficiency is associated with decreased microvascular density and exacerbates hypertension-induced microvascular rarefaction both in the hippocampus and the neocortex. The anti-angiogenic hippocampal gene expression signature observed in hypertensive IGF-1 deficient mice in the present study provides important clues for subsequent studies to elucidate mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of VCI. In conclusion, adult-onset, isolated endocrine IGF-1 deficiency exerts deleterious effects on the cerebral microcirculation, leading to a significant decline in cortical and hippocampal capillarity and exacerbating hypertension-induced cerebromicrovascular rarefaction. The morphological impairment of the cerebral microvasculature induced by IGF-1 deficiency and hypertension reported here, in combination with neurovascular uncoupling, increased blood-brain barrier disruption and neuroinflammation reported in previous studies likely contribute to the pathogenesis of vascular cognitive impairment in elderly hypertensive humans.


Subject(s)
Aging/metabolism , Hippocampus/blood supply , Hypertension/complications , Insulin-Like Growth Factor I/deficiency , Microvascular Rarefaction/pathology , Neocortex/blood supply , Aging/pathology , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Angiotensin II/adverse effects , Angiotensin II/metabolism , Animals , Biomarkers/blood , Blood-Brain Barrier/metabolism , Cognitive Dysfunction/physiopathology , Gene Expression , Humans , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor I/genetics , Male , Mice , Mice, Inbred C57BL , Microvascular Rarefaction/etiology , RNA, Messenger/metabolism
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