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Daniel G Hackam,
Robert R Quinn,
Pietro Ravani,
Doreen M Rabi,
Kaberi Dasgupta,
Stella S Daskalopoulou,
Nadia A Khan,
Robert J Herman,
Simon L Bacon,
Lyne Cloutier, [......],
Richard Lewanczuk,
George K Dresser,
S Brian Penner,
Robert A Hegele,
Philip A McFarlane,
Mukul Sharma,
Debra J Reid,
Sheldon W Tobe,
Luc Poirier,
Raj S Padwal
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ABSTRACT: We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This year's update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be < 150 mm Hg (Grade C) rather than < 140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.
The Canadian journal of cardiology 03/2013; · 3.36 Impact Factor
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Yuan Zhang,
Maros Elsik,
Amanda J Edgley,
Alison J Cox,
Andrew R Kompa,
Bing Wang,
Christina Yan Ru Tan,
Fay L Khong,
David I Stapleton,
Steven Zammit,
Spencer J Williams, Richard E Gilbert,
Henry Krum,
Darren J Kelly
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ABSTRACT: BACKGROUND: Pathological deposition of extracellular matrix in the non-infarct zone (NIZ) of the ventricle post myocardial infarction (MI) is a key contributor to cardiac remodeling and heart failure. FT011, a novel antifibrotic compound, was evaluated for its efficacy in neonatal cardiac fibroblasts (NCF) and in an experimental MI model. METHODS AND RESULTS: Collagen synthesis in NCF was determined by (3)H-proline incorporation following stimulation with TGF-β or angiotensin II (Ang II). FT011 inhibited collagen synthesis to both agents in a dose dependent manner. In vivo, Sprague Dawley rats underwent left anterior descending coronary artery ligation or sham surgery and were randomized one week later to receive either FT011 (200mg/kg/day) or vehicle for a further 4weeks. Echocardiography and cardiac catheterization were performed, and tissues were collected for histological analysis of collagen, myocyte hypertrophy, interstitial macrophage accumulation and Smad2 phosphorylation. mRNA expression of collagens I and III and TGF-β was measured using in situ hybridization and RT-PCR, respectively. FT011 treatment was associated with improved cardiac function (increased ejection fraction, fraction shortening and preload recruitable stroke work) and myocardial remodeling (reduced left ventricular diameter and volume at both end diastolic and systolic) compared with vehicle treatment. FT011 significantly reduced collagen matrix deposition, myocyte hypertrophy and interstitial macrophage infiltration, and mRNA expression of collagens I and III in NIZ compared with vehicle treatment. CONCLUSION: Anti-fibrotic therapy with FT011 in MI rats attenuated fibrosis and preserved systolic function.
International journal of cardiology 12/2012; · 7.08 Impact Factor
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ABSTRACT: Impaired endothelial repair is a key contributor to microvascular rarefaction and consequent end-organ dysfunction in diabetes. Recent studies suggest an important role for bone marrow-derived early outgrowth cells (EOCs) in mediating endothelial repair, but the function of these cells is impaired in diabetes, as in advanced age. We sought to determine whether diabetes-associated EOC dysfunction might be attenuated by pharmacological activation of silent information regulator protein 1 (SIRT1), a lysine deacetylase implicated in nutrient-dependent life span extension in mammals. Despite being cultured in normal (5.5 mM) glucose for 7 days, EOCs from diabetic rats expressed less SIRT1 mRNA, induced less endothelial tube formation in vitro and neovascularization in vivo, and secreted less of the proangiogenic ELR(+) CXC chemokines CXCL1, CXCL3, and CXCL5. Ex vivo SIRT1 activation restored EOC chemokine secretion and increased the in vitro and in vivo angiogenic activity of EOC conditioned medium derived from diabetic animals to levels similar to that derived from control animals. These findings suggest a pivotal role for SIRT1 in diabetes-induced EOC dysfunction and that its pharmacologic activation may provide a new strategy for the restoration of EOC-mediated repair mechanisms.
Stem cells translational medicine. 12/2012; 1(12):921-6.
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ABSTRACT: BACKGROUND: Tranilast has been shown to inhibit TGFβ1-related fibrosis and organ failure in various disease models. We sought to examine the effects of tranilast on left ventricular (LV) remodelling post-MI. METHODS: Following coronary artery ligation, Sprague Dawley rats were randomised to receive tranilast (300mg/kg/d, p.o.) or vehicle control over one of two treatment periods: (1) from 24h until 7 days post-MI, (2) from 7 days to 28 days post-MI. Cardiac tissue was harvested for molecular, immunohistochemical and cell culture analyses. RESULTS: Tranilast treatment of MI rats from 24h until 7 days post-MI reduced myocardial collagen content, α1 (I) procollagen, TGFβ1 and CTGF mRNA transcripts, monocyte/macrophage infiltration and exacerbated infarct expansion compared with vehicle-treatment. Delaying the commencement of tranilast treatment to 7 days post-MI attenuated myocardial fibrosis, gene expression of α1(I) procollagen, α1(III) procollagen, fibronectin, TGFβ1 and CTGF mRNA transcripts, and monocyte/macrophage infiltration at 28d compared to vehicle-treatment, without detriment to infarct healing. Extended post-MI also preserved LV infarct size. In cultures of rat cardiac fibroblasts, tranilast attenuated TGFβ1-stimulated fibrogenesis. CONCLUSION: Tranilast inhibits myocardial TGFβ1 expression, fibrosis in rat post-MI and collagen production in cardiac fibroblasts. While tranilast intervention from 24h post-MI exacerbated infarct expansion, delaying the commencement of treatment to 7 days post-MI impeded LV remodelling.
Heart Lung & Circulation 09/2012; · 1.20 Impact Factor
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ABSTRACT: Cell-based therapy, designed to promote angiogenesis and improve organ function, has been under investigation for the treatment of ischemic heart disease for more than 10 years. Although believed to work primarily by repairing the microvasculature, this form of therapy has not been examined in the setting of chronic kidney disease caused by diabetes in which capillary rarefaction plays a pivotal pathogenetic role. Indeed, despite disease-associated dysfunction, the favorable safety profile of autologous, bone marrow-derived angiogenic cells and their efficacy in animal studies of chronic kidney disease would seem to provide a basis for clinical trials in advanced diabetic nephropathy.
Seminars in Nephrology 09/2012; 32(5):486-93. · 2.12 Impact Factor
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Canadian family physician Medecin de famille canadien 06/2012; 58(6):634-6. · 1.19 Impact Factor
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ABSTRACT: Cell therapy has been extensively investigated in heart disease but less so in the kidney. We considered whether cell therapy also might be useful in diabetic kidney disease. Cognizant of the likely need for autologous cell therapy in humans, we sought to assess the efficacy of donor cells derived from both healthy and diabetic animals. Eight-week-old db/db mice were randomized to receive a single intravenous injection of PBS or 0.5 × 10(6) early-outgrowth cells (EOCs) from db/m or db/db mice. Effects were assessed 4 weeks after cell infusion. Untreated db/db mice developed mesangial matrix expansion and tubular epithelial cell apoptosis in association with increased reactive oxygen species (ROS) and overexpression of thioredoxin interacting protein (TxnIP). Without affecting blood glucose or blood pressure, EOCs not only attenuated mesangial and peritubular matrix expansion, as well as tubular apoptosis, but also diminished ROS and TxnIP overexpression in the kidney of db/db mice. EOCs derived from both diabetic db/db and nondiabetic db/m mice were equally effective in ameliorating kidney injury and oxidative stress. The similarly beneficial effects of cells from healthy and diabetic donors highlight the potential of autologous cell therapy in the related clinical setting.
Diabetes 05/2012; 61(8):2114-25. · 8.29 Impact Factor
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Stella S Daskalopoulou,
Nadia A Khan,
Robert R Quinn,
Marcel Ruzicka,
Donald W McKay,
Daniel G Hackam,
Simon W Rabkin,
Doreen M Rabi, Richard E Gilbert,
Raj S Padwal, [......],
Richard Lewanczuk,
George K Dresser,
Brian Penner,
Robert A Hegele,
Philip A McFarlane,
Mukul Sharma,
Norman R C Campbell,
Debra Reid,
Luc Poirier,
Sheldon W Tobe
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ABSTRACT: We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2012. The new recommendations are: (1) use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome; (2) mineralocorticoid receptor antagonists may be used in selected patients with hypertension and systolic heart failure; (3) a history of atrial fibrillation in patients with hypertension should not be a factor in deciding to prescribe an angiotensin-receptor blocker for the treatment of hypertension; and (4) the blood pressure target for patients with nondiabetic chronic kidney disease has now been changed to < 140/90 mm Hg from < 130/80 mm Hg. We also reviewed the recent evidence on blood pressure targets for patients with hypertension and diabetes and continue to recommend a blood pressure target of less than 130/80 mm Hg.
The Canadian journal of cardiology 05/2012; 28(3):270-87. · 3.36 Impact Factor
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Yuan Zhang,
Amanda J Edgley,
Alison J Cox,
Andrew K Powell,
Bing Wang,
Andrew R Kompa,
David I Stapleton,
Steven C Zammit,
Spencer J Williams,
Henry Krum, Richard E Gilbert,
Darren J Kelly
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ABSTRACT: Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti-fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren-2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans.
Homozygous Ren-2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm(2); P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope-mmHg; P < 0.05), and reduced end-diastolic pressure-volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope-mmHg/μL; P < 0.05).
A direct anti-fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.
European Journal of Heart Failure 03/2012; 14(5):549-62. · 4.90 Impact Factor
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ABSTRACT: The long-term complications of diabetes are characterized by pathologic changes in both the microvasculature and conduit vessels. Although the fenestrated glomerular endothelium classically has been viewed as providing little in the way of an impediment to macromolecular flow, increasing evidence illustrates that this is not the case. Rather, hyperglycemia-mediated endothelial injury may predispose to albuminuria in diabetes both through direct effects and through bidirectional communication with neighboring podocytes. Although neo-angiogenesis of the glomerular capillaries may be a feature of early diabetes, particularly in the experimental setting, loss of capillaries in the glomerulus and in the interstitium are key events that each correlate closely with declining glomerular filtration rate in patients with diabetic nephropathy. The hypoxic milieu that follows the microvascular rarefaction provides a potent stimulus for fibrogenesis, leading to the glomerulosclerosis and tubulointerstitial fibrosis that characterize advanced diabetic kidney disease. Given the pivotal role the endothelium plays in both the development and the progression of diabetic nephropathy we need effective strategies that prevent its loss or accelerate its regeneration. Such advances likely will lead not only to improved tissue oxygenation and reduced fibrosis, but also to improved long-term renal function.
Seminars in Nephrology 03/2012; 32(2):199-207. · 2.12 Impact Factor
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ABSTRACT: Endothelial injury is a characteristic finding in chronic kidney disease and is associated with both markedly increased cardiovascular risk and chronic kidney disease progression. The past decade has seen a remarkable surge of interest in the role of bone marrow-derived cells for the protection, repair, and regeneration of injured endothelium. In particular, despite controversies regarding their mechanisms of action, endothelial progenitor cells have garnered considerable attention, with multiple reports suggesting that these cells exhibit remarkable pro-angiogenic effects. Recent advances in our understanding of how the bone marrow responds to endothelial injury now suggest that multiple bone marrow cell populations, including both endothelial progenitor cells and a novel group of cells called early outgrowth cells, promote endothelial repair and regeneration through different, yet complementary, mechanisms. Moreover, certain subsets of bone marrow-derived cells also appear to have novel, potent, angiogenesis-independent tissue-protective properties. The bone marrow should thus now be viewed not only as a hematopoiesis organ, but also as a rich reservoir of cells capable of protecting and even regenerating nonhematopoietic tissues such as the kidney. To harness the prognostic and therapeutic potential of the bone marrow, the renal community must be aware of recent advances in our understanding of the nature and therapeutic potential of these cells.
Seminars in Nephrology 03/2012; 32(2):215-23. · 2.12 Impact Factor
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ABSTRACT: BACKGROUND/AIMSBACKGROUND/AIMS: While experimental models that emulate diabetic nephropathy are valuable tools for elucidating pathogenetic mechanisms and developing novel therapies, existing models imperfectly recapitulate human disease. In diabetes, hyperglycemia and hemodynamic forces act in concert to induce renal injury. Accordingly, in the present study, we combined streptozotocin-induced diabetes with surgical ablation of 5/6 of the kidney mass with the aim of evaluating their additive effects on renal function and glomerular morphology.
Female F344 rats were randomized to undergo subtotal nephrectomy (SNx) either at baseline or following 4 weeks of diabetes.
In comparison to sham rats, rats with diabetes or rats after SNx surgery, diabetic subtotally nephrectomized (DM-SNx) rats demonstrated an increase in systolic blood pressure, glomerular volume and mesangial matrix. Albuminuria was synergistically increased by hyperglycemia and renal mass ablation associated with decreased nephrin expression. In contrast, glomerular capillary rarefaction and glomerular filtration rate were similarly reduced in SNx and DM-SNx rats.
The DM-SNx rat recapitulates some of the features of human disease, most notably augmented albuminuria. Since this model avoids the deletion or overexpression of gene(s) linked to the pathogenesis of nephropathy, the DM-SNx rat model represents a complementary tool for the trial of novel therapies.
Nephron extra. 01/2012; 2(1):115-24.
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ABSTRACT: Locally-active growth factors have been implicated in the pathogenesis of many diseases in which organ fibrosis is a characteristic feature. In the setting of chronic kidney disease (CKD), two such pro-fibrotic factors, transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF) have emerged as lead potential targets for intervention. Given the incomplete organ protection afforded by blocking the actions of TGF-ß or PDGF individually, we sought to determine whether an agent that inhibited the actions of both may have broader effects in ameliorating the key structural and functional abnormalities of CKD.
Accordingly, we studied the effects of a recently described, small molecule anti-fibrotic drug, 3-methoxy-4-propargyloxycinnamoyl anthranilate (FT011, Fibrotech Therapeutics, Australia), which should have these effects.
In the in vitro setting, FT011 inhibited both TGF-ß1 and PDGF-BB induced collagen production as well as PDGF-BB-mediated mesangial proliferation. Consistent with these in vitro actions, when studied in a robust model of non-diabetic kidney disease, the 5/6 nephrectomised rat, FT011 attenuated the decline in GFR, proteinuria and glomerulosclerosis (p<0.05 for all). Similarly, in the streptozotocin-diabetic Ren-2 rat, a model of advanced diabetic nephropathy, FT011 reduced albuminuria, glomerulosclerosis and tubulointerstitial fibrosis.
Together these studies suggest that broadly antagonising growth factor actions, including those of TGF-ß1 and PDGF-BB, has the potential to protect the kidney from progressive injury in both the diabetic and non-diabetic settings.
PLoS ONE 01/2012; 7(10):e47160. · 4.09 Impact Factor
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ABSTRACT: To summarize the evidence for the need to improve pharmacologic management of hypertension in people with type 2 diabetes and to provide expert advice on how blood pressure (BP) treatment can be improved in primary care.
Studies were obtained by performing a systematic review of the literature on hypertension and diabetes, from which management recommendations were developed, reviewed, and voted on by a group of experts selected by the Canadian Hypertension Education Program and the Canadian Diabetes Association; authors' expert opinions on optimal pharmacologic management were also considered during this process.
The pathogenesis of hypertension in patients with diabetes is complex, involving a range of biological and environmental factors and genetic predisposition; as a result, hypertension in people with diabetes incurs higher associated risks and adverse events. Mortality and morbidity are heightened in diabetes patients who do not achieve BP control (ie, a target value of less than 130/80 mm Hg). Large randomized controlled trials and meta-analyses of randomized controlled trials have shown that reducing BP pharmacologically is single-handedly the most effective way to reduce rates of death and disability in patients with diabetes, particularly associated cardiovascular risks. Often, combinations of 2 or more drugs (diuretics, angiotensin-converting enzyme inhibitors, β-blockers, angiotensin receptor blockers, calcium channel blockers, spironolactone, etc) are required for pharmacotherapy to be effective, particularly for patients in whom BP is difficult to control. However, the health care costs associated with extensively lowering BP are substantially less than the costs associated with treating the complications that can be prevented by lowering BP.
Detecting and managing hypertension in people with diabetes is one of the most effective measures to prevent adverse events, and pharmacotherapy is one of the most effective ways to maintain target BP levels in primary care.
Canadian family physician Medecin de famille canadien 09/2011; 57(9):997-1002, e347-53. · 1.19 Impact Factor
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ABSTRACT: 1. Aliskiren is a renin inhibitor with an IC(50) of 0.6 nmol/L for human renin, 4.5 nmol/L for mouse renin and 80 nmol/L for rat renin. 2. In the present study, we compared the effects of aliskiren (10 mg/kg per day), the angiotensin-converting enzyme inhibitor perindopril (0.2 mg/kg per day) and their combination on angiotensin and bradykinin peptides in female heterozygous (mRen-2)27 rats, transgenic for the mouse renin gene. 3. All three treatments produced similar reductions in systolic blood pressure, heart weight and plasma aldosterone levels and reduced angiotensin II levels in lung, but only perindopril and the combination reduced angiotensin II levels in kidney of (mRen-2)27 rats. In contrast, aliskiren and the combination, but not perindopril alone, increased cardiac bradykinin levels. Aliskiren increased immunostaining for tissue kallikrein in the heart and reduced cardiac fibrosis. 4. We investigated the mechanism underlying the increase in bradykinin levels following aliskiren treatment in Sprague-Dawley rats, in which aliskiren has a lower potency for renin inhibition. Aliskiren (10 mg/kg per day) reduced renal angiotensin levels within 24 h, but treatment for > 24 h was required to increase cardiac bradykinin levels. Moreover, 3 mg/kg per day aliskiren increased cardiac bradykinin levels, but did not reduce renal angiotensin levels. Aliskiren did not potentiate the hypotensive effects of bradykinin; however, it increased tissue kallikrein, but not plasma kallikrein, mRNA levels in the heart. 5. These data demonstrate that the aliskiren-induced increase in cardiac bradykinin levels is independent of renin inhibition and changes in bradykinin metabolism, but is associated with increased tissue kallikrein gene expression.
Clinical and Experimental Pharmacology and Physiology 07/2011; 38(9):623-31. · 1.85 Impact Factor
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Kim A Connelly,
Andrew Advani,
Sandra Kim,
Suzanne L Advani,
Michael Zhang,
Kathryn E White,
Young M Kim,
Colleen Parker,
Kerri Thai,
Henry Krum,
Darren J Kelly, Richard E Gilbert
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ABSTRACT: The pro(renin) receptor is a 350 amino acid transmembrane protein, that on ligand binding, increases the catalytic efficiency of angiotensinogen cleavage by both prorenin and renin, augmenting angiotensin I formation at the cell surface. While implicated in a broad range of diseases, studies to date have focused on the kidney, particularly in the diabetic context. We sought to examine the site-specific expression of the pro(renin) receptor within the heart.
Using confocal microscopy, site-specific markers and transmission electron microscopy we assessed the location of the pro(renin) receptor in the heart at both cellular/sub-cellular levels. We assessed pro(renin) receptor expression in the setting of disease and blockade of the renin-angiotensin system, using the TGR[m(Ren2)-27] model of diabetic cardiomyopathy and the direct renin inhibitor, aliskiren.
The pro(renin) receptor was found predominantly at the Z-disc and dyad of cardiac myocytes coinciding closely with the distributions of the vacuolar H⁺-ATPase and ryanodine receptor, known to be located within T-tubules and the sarcoplasmic reticulum's terminal cisternae, respectively. Pro(renin) receptor mRNA/protein abundance were increased ∼3-fold in the hearts of diabetic rats in association with diastolic dysfunction, myocyte hypertrophy and interstitial fibrosis (all P < 0.01). Direct renin inhibition reduced cardiac pro(renin) receptor expression in association with improved cardiac structure/function (all P < 0.05).
Together, these findings are consistent with the notion that the pro(renin) receptor is a component of the vacuolar H⁺-ATPase, and that like the latter, is increased in the setting of cardiac stress and lowered by the administration of an ostensibly cardioprotective agent.
Journal of hypertension 06/2011; 29(6):1175-84. · 4.02 Impact Factor
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ABSTRACT: Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy where therapy targeting the β isoform of this enzyme has been examined. However, PKC-β is also increased in various forms of human glomerulonephritis, including IgA nephropathy. Accordingly, we sought to examine the effects of PKC-β inhibition in the Thy1.1 model of mesangial proliferative glomerulonephritis.
Following administration of monoclonal OX-7, anti-rat Thy-1.1 antibody, Male Wistar rats were randomized to receive either the PKC-β inhibitor, ruboxistaurin (10 mg/kg per day in chow) or vehicle. Animals were then examined 6 days later.
PKC-β inhibition was associated with reductions in mesangial cellularity and extracellular matrix deposition. Proteinuria was, however, unaffected. In vitro, PKC-β inhibition showed modest, dose-dependent reductions in mesangial cell (3) H-thymidine and (3) H-proline incorporations, indices of cell proliferation and collagen synthesis, respectively.
The amelioration of the pathological findings of experimental mesangial proliferative glomerulonephritis by PKC-β inhibition suggests the potential clinical utility of this approach as a therapeutic strategy in non-diabetic glomerular disease.
Nephrology 05/2011; 16(7):649-55. · 1.31 Impact Factor
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ABSTRACT: Epigenetic changes in gene expression play a role in the development of diabetic complications, including nephropathy. Histone deacetylases (HDACs) are a group of enzymes that exert epigenetic effects by altering the acetylation status of histone and nonhistone proteins. In the current study, we investigated the action of the clinically available HDAC inhibitor vorinostat in a mouse model of diabetic nephropathy, with the following aims: to define its effect on the progression of renal injury and to explore its mechanism of action by focusing on its role in regulating the expression of endothelial nitric oxide synthase (eNOS). Control and streptozotocin-diabetic wild-type and eNOS(-/-) mice were treated with vorinostat by daily oral dosing for 18 weeks. Without affecting either blood glucose concentration or blood pressure, vorinostat decreased albuminuria, mesangial collagen IV deposition, and oxidative-nitrosative stress in streptozotocin-wild-type mice. These attenuating effects were associated with a >50% reduction in eNOS expression in mouse kidneys and in cultured human umbilical vein endothelial cells. Vorinostat treatment had no effect on albuminuria, glomerular collagen IV concentration, or mesangiolysis in diabetic mice genetically deficient in eNOS. These observations illustrate the therapeutic efficacy of long-term HDAC inhibition in diabetic nephropathy and emphasize the importance of the interplay between eNOS activity and oxidative stress in mediating these effects.
American Journal Of Pathology 05/2011; 178(5):2205-14. · 4.89 Impact Factor
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ABSTRACT: Clinical trials and experimental studies have highlighted the importance of epigenetic processes in the development of diabetic complications. One of the earliest features of diabetic nephropathy is renal enlargement. The epidermal growth factor (EGF) has a pivotal role in the development of diabetic nephromegaly and transactivation of its receptor has been implicated in the pathogenesis of later-stage disease. As EGF signaling is altered by the acetylation status of histone proteins, we measured the effects of the histone deacetylase (HDAC) inhibitor, vorinostat, in mediating renal enlargement in diabetes focusing on the EGF-EGF receptor (EGFR) axis. In cultured proximal tubule (normal rat kidney) cells, vorinostat treatment reduced EGFR protein and mRNA, and attenuated cellular proliferation. Within 72 h of diabetes induction with streptozotocin, urinary EGF excretion was increased approximately threefold and was unaffected by vorinostat, even though the kidneys of vorinostat-treated diabetic rats had reduced tubular epithelial cell proliferation. Daily treatment of diabetic rats with vorinostat for 4 weeks blunted renal growth and glomerular hypertrophy. Thus, early renal changes in diabetes are amenable to epigenetic intervention. Attenuating effects of HDAC inhibition, although multifactorial, are likely to be mediated in part through downregulation of the EGFR.
Kidney International 03/2011; 79(12):1312-21. · 6.61 Impact Factor
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Andrew Advani,
Kim A Connelly,
Darren A Yuen,
Yanling Zhang,
Suzanne L Advani,
Judy Trogadis,
M Golam Kabir,
Etai Shachar,
Michael A Kuliszewski,
Howard Leong-Poi,
Duncan J Stewart, Richard E Gilbert
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ABSTRACT: Rarefaction of the renal microvasculature correlates with declining kidney function. However, current technologies commonly used for its evaluation are limited by their reliance on endothelial cell antigen expression and assessment in two dimensions. We set out to establish a widely applicable and unbiased optical sectioning method to enable three dimensional imaging and reconstruction of the renal microvessels based on their luminal filling. The kidneys of subtotally nephrectomized (SNx) rats and their sham-operated counterparts were subjected to either routine two-dimensional immunohistochemistry or the novel technique of fluorescent microangiography (FMA). The latter was achieved by perfusion of the kidney with an agarose suspension of fluorescent polystyrene microspheres followed by optical sectioning of 200 µm thick cross-sections using a confocal microscope. The fluorescent microangiography method enabled the three-dimensional reconstruction of virtual microvascular casts and confirmed a reduction in both glomerular and peritubular capillary density in the kidneys of SNx rats, despite an overall increase in glomerular volume. FMA is an uncomplicated technique for evaluating the renal microvasculature that circumvents many of the limitations imposed by conventional analysis of two-dimensional tissue sections.
PLoS ONE 01/2011; 6(10):e24695. · 4.09 Impact Factor
