Publications by authors named "Bryan R Conway"

22 Publications

  • Page 1 of 1

A National Registry Study of Patient and Renal Survival in Adult Nephrotic Syndrome.

Kidney Int Rep 2021 Feb 4;6(2):449-459. Epub 2020 Nov 4.

Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh Bioquarter, Edinburgh, Scotland, UK.

Introduction: We aimed to determine the mortality rate, cause of death, and rate of end-stage kidney disease (ESKD) in adults with nephrotic syndrome (NS).

Methods: We conducted a national registry-based study, including all 522 adults who had a kidney biopsy for NS in Scotland in 2014-2017. We linked the Scottish Renal Registry to death certificate data. We performed survival and Cox proportional hazards analyses, accounting for competing risks of death and ESKD. We compared mortality rates with those in the age- and sex-matched general population.

Results: A total of 372 patients had primary NS; 150 had secondary NS. Over a median follow-up of 866 days, 110 patients (21%) died. In patients with primary NS, observed versus population 3-year mortality was 2.1% (95% CI 0.0%-4.6%) versus 0.9% (0.8%-1.0%) in patients aged <60 years and 24.9% (18.4%-30.8%) versus 9.4% (8.3%-10.5%) in those aged ≥60 years. In secondary NS, this discrepancy was 17.1% (5.6%-27.2%) versus 1.1% (0.9%-1.2%) in <60-year-olds and 49.4% (36.6%-59.7%) versus 8.1% (6.6%-9.6%) in ≥60-year-olds. In primary NS, cardiovascular causes accounted for 28% of deaths, compared with 18% in the general population. Eighty patients (15%) progressed to ESKD. Incidence of ESKD by 3 years was 8.4% (95% CI 4.9%-11.7%) in primary and 35.1% (24.3%-44.5%) in secondary NS. Early remission of proteinuria and the absence of early acute kidney injury (AKI) were associated with lower rates of death and ESKD.

Conclusions: Adults with NS have high rates of death and ESKD. Cardiovascular causes account for excess mortality in primary NS.
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http://dx.doi.org/10.1016/j.ekir.2020.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879209PMC
February 2021

Identifying cell-enriched miRNAs in kidney injury and repair.

JCI Insight 2020 12 17;5(24). Epub 2020 Dec 17.

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-β+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients.
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http://dx.doi.org/10.1172/jci.insight.140399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819746PMC
December 2020

Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease.

J Am Soc Nephrol 2020 12 25;31(12):2833-2854. Epub 2020 Sep 25.

Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

Background: Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.

Methods: Integrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.

Results: A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses , before transitioning to become macrophages that accumulate in late injury. Conversely, a novel macrophage subset acts during repair.

Conclusions: Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
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http://dx.doi.org/10.1681/ASN.2020060806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790206PMC
December 2020

Endothelin-1 Mediates the Systemic and Renal Hemodynamic Effects of GPR81 Activation.

Hypertension 2020 05 23;75(5):1213-1222. Epub 2020 Mar 23.

From the University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Scotland, United Kingdom (N.K.J., K.S., A.C., R.I.M., A.T., C.M.M., C.C., B.R.C., L.D., D.E.W.L., P.W.H., D.J.W., N.D., J.W.D., J.J.M., M.A.B.).

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in mice. mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176350PMC
May 2020

Cardiovascular disease biomarkers are associated with declining renal function in type 2 diabetes.

Diabetologia 2017 08 20;60(8):1400-1408. Epub 2017 May 20.

Centre for Population Health Sciences, University of Edinburgh, Old Medical School, Teviot Place, Edinburgh, EH8 9AG, UK.

Aims/hypothesis: We investigated whether biochemical cardiovascular risk factors and/or markers of subclinical cardiovascular disease were associated with the development of reduced renal function in people with type 2 diabetes.

Methods: A cohort of 1066 Scottish men and women aged 60-74 years with type 2 diabetes from the Edinburgh Type 2 Diabetes Study were followed up for a median of 6.7 years. New-onset reduced renal function was defined as two eGFRs <60 ml min (1.73 m) at least 3 months apart with a > 25% decline from baseline eGFR. Ankle brachial pressure index (ABI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) were measured at baseline. Pulse wave velocity (PWV) and carotid intima media thickness were measured 1 year into follow-up. Data were analysed using Cox proportional hazards models.

Results: A total of 119 participants developed reduced renal function during follow-up. ABI, PWV, NT-proBNP and hsTnT were all associated with onset of decline in renal function following adjustment for age and sex. These associations were attenuated after adjustment for additional diabetes renal disease risk factors (systolic BP, baseline eGFR, albumin:creatinine ratio and smoking pack-years), with the exception of hsTnT which remained independently associated (HR 1.51 [95% CI 1.22, 1.87]). Inclusion of hsTnT in a predictive model improved the continuous net reclassification index by 0.165 (0.008, 0.286).

Conclusions/interpretation: Our findings demonstrate an association between hsTnT, a marker of subclinical cardiac ischaemia, and subsequent renal function decline. Further research is required to establish the predictive value of hsTnT and response to intervention.
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http://dx.doi.org/10.1007/s00125-017-4297-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491560PMC
August 2017

Renal disease pathophysiology and treatment: contributions from the rat.

Dis Model Mech 2016 12;9(12):1419-1433

University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

The rat has classically been the species of choice for pharmacological studies and disease modeling, providing a source of high-quality physiological data on cardiovascular and renal pathophysiology over many decades. Recent developments in genome engineering now allow us to capitalize on the wealth of knowledge acquired over the last century. Here, we review rat models of hypertension, diabetic nephropathy, and acute and chronic kidney disease. These models have made important contributions to our understanding of renal diseases and have revealed key genes, such as Ace and P2rx7, involved in renal pathogenic processes. By targeting these genes of interest, researchers are gaining a better understanding of the etiology of renal pathologies, with the promised potential of slowing disease progression or even reversing the damage caused. Some, but not all, of these target genes have proved to be of clinical relevance. However, it is now possible to generate more sophisticated and appropriate disease models in the rat, which can recapitulate key aspects of human renal pathology. These advances will ultimately be used to identify new treatments and therapeutic targets of much greater clinical relevance.
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http://dx.doi.org/10.1242/dmm.027276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200898PMC
December 2016

Wnt6: another player in the yin and yang of renal Wnt signaling.

Am J Physiol Renal Physiol 2016 08 8;311(2):F404-5. Epub 2016 Jun 8.

Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, United Kingdom

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http://dx.doi.org/10.1152/ajprenal.00296.2016DOI Listing
August 2016

Urinary peptidomics in a rodent model of diabetic nephropathy highlights epidermal growth factor as a biomarker for renal deterioration in patients with type 2 diabetes.

Kidney Int 2016 May 7;89(5):1125-1135. Epub 2016 Mar 7.

University of Edinburgh/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; Department of Renal Medicine, Royal Infirmary, Edinburgh, UK. Electronic address:

Many diabetic patients suffer from declining renal function without developing albuminuria. To identify alternative biomarkers for diabetic nephropathy (DN) we performed urinary peptidomic analysis in a rodent model in which hyperglycemia and hypertension synergize to promote renal pathologic changes consistent with human DN. We identified 297 increased and 15 decreased peptides in the urine of rats with DN compared with controls, including peptides derived from proteins associated with DN and novel candidate biomarkers. We confirmed by ELISA that one of the parent proteins, urinary epidermal growth factor (uEGF), was more than 2-fold reduced in rats with DN in comparison with controls. To assess the clinical utility of uEGF we examined renal outcomes in 642 participants from the Edinburgh Type 2 Diabetes Study who were normoalbuminuric and had preserved renal function at baseline. After adjustment for established renal risk factors, a lower uEGF to creatinine ratio was associated with new-onset estimated glomerular filtration rate less than 60 ml/min per 1.73m(2) (odds ratio 0.48; 95% confidence interval, 0.26-0.90), rapid (over 5% per annum) decline in renal function (odds ratio 0.44; 95% confidence interval, 0.27-0.72) or the composite of both outcomes (odds ratio 0.38; 95% confidence interval, 0.24-0.62). Thus, the utility of a low uEGF to creatinine ratio as a biomarker of progressive decline in renal function in normoalbuminuric patients should be assessed in additional populations.
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http://dx.doi.org/10.1016/j.kint.2016.01.015DOI Listing
May 2016

An Update on the Use of Animal Models in Diabetic Nephropathy Research.

Curr Diab Rep 2016 Feb;16(2):18

Centre for Cardiovascular Science, Queen's Medical Research Centre, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland.

In the current review, we discuss limitations and recent advances in animal models of diabetic nephropathy (DN). As in human disease, genetic factors may determine disease severity with the murine FVB and DBA/2J strains being more susceptible to DN than C57BL/6J mice. On the black and tan, brachyuric (BTBR) background, leptin deficient (ob/ob) mice develop many of the pathological features of human DN. Hypertension synergises with hyperglycemia to promote nephropathy in rodents. Moderately hypertensive endothelial nitric oxide synthase (eNOS(-/-)) deficient diabetic mice develop hyaline arteriosclerosis and nodular glomerulosclerosis and induction of renin-dependent hypertension in diabetic Cyp1a1mRen2 rats mimics moderately severe human DN. In addition, diabetic eNOS(-/-) mice and Cyp1a1mRen2 rats recapitulate many of the molecular pathways activated in the human diabetic kidney. However, no model exhibits all the features of human DN; therefore, researchers should consider biochemical, pathological, and transcriptomic data in selecting the most appropriate model to study their molecules and pathways of interest.
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http://dx.doi.org/10.1007/s11892-015-0706-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729785PMC
February 2016

Mineralocorticoid Excess or Glucocorticoid Insufficiency: Renal and Metabolic Phenotypes in a Rat Hsd11b2 Knockout Model.

Hypertension 2015 Sep 15;66(3):667-73. Epub 2015 Jun 15.

From the Molecular Physiology Laboratory, University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom.

Obesity and hypertension are 2 major health issues of the 21st century. The syndrome of apparent mineralocorticoid excess is caused by deficiency of 11β-hydroxysteroid dehydrogenase type 2 (Hsd11b2), which normally inactivates glucocorticoids, rendering the mineralocorticoid receptor aldosterone-specific. The metabolic consequences of Hsd11b2 knockout in the rat are investigated in parallel with electrolyte homeostasis. Hsd11b2 was knocked out, by pronuclear microinjection of targeted zinc-finger nuclease mRNAs, and 1 line was characterized for its response to renal and metabolic challenges. Plasma 11-dehydrocorticosterone was below detection thresholds, and Hsd11b2 protein was undetected by Western blot, indicating complete ablation. Homozygotes were 13% smaller than wild-type littermates, and were polydipsic and polyuric. Their kidneys, adrenals, and hearts were significantly enlarged, but mesenteric fat pads and liver were significantly smaller. On a 0.3% Na diet, mean arterial blood pressure was ≈65 mm Hg higher than controls but only 25 mm Hg higher on a 0.03% Na(+) diet. Urinary Na/K ratio of homozygotes was similar to controls on 0.3% Na(+) diet but urinary albumin and calcium were elevated. Corticosterone and aldosterone levels showed normal circadian variation on both a 0.3% and 0.03% Na(+) diet, but plasma renin was suppressed in homozygotes on both diets. Plasma glucose responses to an oral glucose challenge were reduced despite low circulating insulin, indicating much greater sensitivity to insulin in homozygotes. The rat model reveals mechanisms linking electrolyte homeostasis and metabolic control through the restriction of Hsd11b1 substrate availability.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847935PMC
September 2015

Vascular and inflammatory actions of P2X receptors in renal injury.

Auton Neurosci 2015 Sep 9;191:135-40. Epub 2015 May 9.

British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom. Electronic address:

P2 purinergic receptors are activated by extracellular ATP and subserve a plethora of roles in the body, including metabolism, inflammation and neuronal signalling. This review focuses on renal purinergic receptors and how different roles that they play may contribute to renal dysfunction and the progression of chronic kidney disease. Numerous studies have linked P2 receptors, particularly the P2X4R and P2X7R subtypes, to kidney injury and damage. However, the mechanisms underlying this association are not fully defined. Several studies show that activation of P2X4R and particularly P2X7R can have a pro-inflammatory effect, causing or exacerbating damage to renal tissue. However, clinical trials aiming to utilise P2X7R antagonists to treat inflammatory disease have been unsuccessful, and it is possible that other mechanisms besides inflammation tie P2X7R activation to disease progression. In this context, purinergic signalling is also involved in the control of vascular tone and our recent studies suggest that activation of P2X4R/P2X7R causes renal vascular dysfunction and contributes to chronic kidney disease. This brief review aims to summarise the complementary inflammatory and vascular roles of P2X receptors in the kidney, with emphasis on the subtypes P2X4R and P27XR, and how each contributes to and presents therapeutic targets in the progression of chronic kidney disease.
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http://dx.doi.org/10.1016/j.autneu.2015.05.001DOI Listing
September 2015

Balloon angioplasty, with and without stenting, versus medical therapy for hypertensive patients with renal artery stenosis.

Cochrane Database Syst Rev 2014 5(12):CD002944. Epub 2014 Dec 5.

Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK.

Background: Atherosclerotic renal artery stenosis is the most common cause of secondary hypertension. Balloon angioplasty with stenting is widely used for the treatment of hypertensive patients with renal artery stenosis but the effectiveness of this procedure in treating hypertension, improving renal function and preventing adverse cardiovascular and renal events remains uncertain. This is an update, to include the results of recent, important large trials, of a review first published in 2003.

Objectives: To compare the effectiveness of balloon angioplasty (with and without stenting) with medical therapy for the treatment of atherosclerotic renal artery stenosis in patients with hypertension. The following outcomes were compared: blood pressure control, renal function, frequency of cardiovascular and renal adverse events, presence or absence of restenosis of the renal artery, side effects of medical therapy, numbers and defined daily doses of antihypertensive drugs.

Search Methods: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2014) and CENTRAL (2014, Issue 4). Bibliographies were also reviewed and trial authors were contacted for more information.

Selection Criteria: Randomised controlled trials (RCTs) comparing balloon angioplasty with medical therapy in hypertensive patients with haemodynamically significant renal artery stenosis (greater than 50% reduction in luminal diameter) and with a minimum follow-up of six months.

Data Collection And Analysis: Data were extracted independently on trial design, participants, interventions and outcome measures. A formal meta-analysis was completed to assess the effect on blood pressure, renal function and cardiovascular and renal adverse events. Peto's odds ratios (ORs) and corresponding 95% confidence intervals (CI) for dichotomous outcomes and mean differences (MD) and corresponding 95% CIs for continuous variables were calculated.

Main Results: Eight RCTs involving 2222 participants with renal artery stenosis were included in the review. The overall quality of evidence included in this review was moderate. Limited pooling of results was possible due to the variable presentation of some of the trial outcomes. Meta-analysis of the four studies reporting change in diastolic blood pressure (BP) found a small improvement in diastolic BP in the angioplasty group (MD -2.00 mmHg; 95% CI -3.72 to -0.27) whilst the meta-analysis of the five studies reporting change in systolic BP did not find any evidence of significant improvement (MD -1.07 mmHg; 95% CI -3.45 to 1.30). There was no significant effect on renal function as measured by serum creatinine (MD -7.99 µmol/L; 95% CI -22.6 to 6.62). Meta-analysis of the three studies that reported the mean number of antihypertensive drugs found a small decrease in antihypertensive drug requirements for the angioplasty group (MD -0.18; 95% CI -0.34 to -0.03). Repeat angiography was only performed on a small number of participants in a single trial and it was therefore not possible to comment on restenosis of the renal artery following balloon angioplasty. Based on the results of the seven studies that reported cardiovascular and renal clinical outcomes there were no differences in cardiovascular (OR 0.91; 95% CI 0.75 to 1.11) or renal adverse events (OR 1.02; 95% CI 0.75 to 1.38) between the angioplasty and medical treatment groups. A small number of procedural complications of balloon angioplasty were reported (haematoma at the site of catheter insertion (6.5%), femoral artery pseudoaneurysm (0.7%), renal artery or kidney perforation or dissection (2.5%) as well as peri-procedural deaths (0.4%)). No side effects of medical therapy were reported.

Authors' Conclusions: The available data are insufficient to conclude that revascularisation in the form of balloon angioplasty, with or without stenting, is superior to medical therapy for the treatment of atherosclerotic renal artery stenosis in patients with hypertension. However, balloon angioplasty results in a small improvement in diastolic blood pressure and a small reduction in antihypertensive drug requirements. Balloon angioplasty appears safe and results in similar numbers of cardiovascular and renal adverse events to medical therapy.
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http://dx.doi.org/10.1002/14651858.CD002944.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138037PMC
January 2015

Tight blood glycaemic and blood pressure control in experimental diabetic nephropathy reduces extracellular matrix production without regression of fibrosis.

Nephrology (Carlton) 2014 Dec;19(12):802-13

Centre for Cardiovascular Science, British Heart Foundation/University of Edinburgh, Edinburgh, UK.

Aims: Regression of albuminuria and renal fibrosis occurs in patients with diabetic nephropathy (DN) following tight control of blood glucose and blood pressure, however the pathways that promote regression remain poorly understood and we wished to characterize these using a rodent model.

Methods: Diabetes was induced with streptozotocin in Cyp1a1mRen2 rats and hypertension was generated by inducing renin transgene expression with dietary indole-3-carbinol (I-3-C) for 28 weeks. At this point an 'injury cohort' was culled, while in a 'reversal cohort' glycaemia was tightly controlled using insulin implants and blood pressure normalized by withdrawing dietary I-3-C for a further 8 weeks. Pathways activated during and following reversal of diabetes and hypertension were assessed by microarray profiling.

Results: Tight control of blood glucose and blood pressure reduced albuminuria and renal hypertrophy, but had no impact on renal fibrosis. 85 genes were up-regulated specifically during the injury phase, including genes encoding multiple myofibroblast and extracellular matrix (ECM) proteins. Conversely, 314 genes remained persistently elevated during reversal including genes linked to innate/adaptive immunity, phagocytosis, lysosomal processing and degradative metalloproteinases (MMPs). Despite increased MMP gene expression, MMP activity was suppressed during both injury and reversal, in association with up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) protein. Physical separation of the TIMP-1/MMP complexes during zymography of tissue homogenate restored MMP activity.

Conclusion: Normalization of blood glucose and pressure ameliorates albuminuria and inhibits excess ECM production, however persistent TIMP-1 expression hinders attempts at ECM remodelling. Therapies which counteract the action of TIMPs may accelerate scar resolution.
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http://dx.doi.org/10.1111/nep.12335DOI Listing
December 2014

Recent advances in animal models of diabetic nephropathy.

Nephron Exp Nephrol 2014 12;126(4):191-5. Epub 2014 Jul 12.

Centres for Inflammation Research, University of Edinburgh, Edinburgh, UK.

Diabetic nephropathy (DN) is the single most common cause of end-stage kidney disease. Therefore, it is imperative that novel therapies are developed. Progress has been hindered, however, by the lack of robust animal models. In the current review we describe recent advances in the field, including the impact of background strain, hypertension and transcriptomic profiling. While the C57BL/6J strain is relatively resistant to DN, the FVB strain appears more susceptible and Ove26 and db/db mice on this background may be useful in modelling types 1 and 2 DN, respectively. Black and tan, brachyury (BTBR) mice deficient for the leptin receptor (ob/ob) develop many of the pathological features of human DN and, remarkably, treatment with exogenous leptin ameliorates hyperglycaemia, albuminuria and glomerulosclerosis. Hypertension plays a key role in the progression of human DN and exacerbates nephropathy in diabetic rodents. Endothelial nitric oxide synthase deficiency (eNOS(-/-)) results in moderate hypertension and the development of nodular glomerulosclerosis and hyaline arteriosclerosis in streptozotocin-induced diabetic C57BL/6J mice. In Cyp1a1mRen2 rats, renin-dependent hypertension synergises with streptozotocin-induced hyperglycaemia to produce a 500-fold increase in albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. Renal transcriptional profiling suggests that many of the gene expression changes observed in human DN are replicated in eNOS(-/-) mice and Cyp1a1mRen2 rats. Despite these advances, no model faithfully recapitulates all the features of human DN and further refinements are required. In the interim, it is likely that researchers may use publically available transcriptomic data to select the most appropriate model to study their molecule or pathway of interest.
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http://dx.doi.org/10.1159/000363300DOI Listing
April 2015

Administration of heme arginate ameliorates murine type 2 diabetes independently of heme oxygenase activity.

PLoS One 2013 30;8(10):e78209. Epub 2013 Oct 30.

Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.

Amelioration of rodent type 2 diabetes by hemin has been linked to increased heme oxygenase (HO) activity, however alternative mechanisms have recently been proposed for its anti-diabetic effect. We sought to determine the anti-diabetic efficacy of heme arginate (HA), a clinically licensed preparation of heme, and whether its predominant mode of action is via increased HO activity. Intravenous administration of HA reduced hyperglycemia in diabetic (db/db) mice. Co-administration of the HO inhibitor stannous (IV) mesoporphyrin IX dichloride (SM) resulted unexpectedly in a further improvement in glycaemic control despite restoring HO activity to baseline levels. The anti-diabetic effects of HA±SM were associated with increased adiposity, increased serum adiponectin levels, reduced adipose tissue and islet inflammation and preservation of islet β-cell function. HO activity independent effects of HA on adipogenesis and β-cell inflammation were further confirmed in cell culture models using the 3T3-L1 pre-adipocyte and MIN6 β-cell lines, respectively. In conclusion, our work demonstrates that the heme component of HA ameliorates experimental type 2 diabetes by promoting metabolically favourable adipogenesis and preserving islet β-cell function, but this is not mediated via increased HO activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813508PMC
February 2015

MicroRNA-214 antagonism protects against renal fibrosis.

J Am Soc Nephrol 2014 Jan 24;25(1):65-80. Epub 2013 Oct 24.

BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;

Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-β signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-β blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-β signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.
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http://dx.doi.org/10.1681/ASN.2013010072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871772PMC
January 2014

Measuring urinary tubular biomarkers in type 2 diabetes does not add prognostic value beyond established risk factors.

Kidney Int 2012 Oct 20;82(7):812-8. Epub 2012 Jun 20.

University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Metabolic Unit, Western General Hospital, Edinburgh, UK.

Tubulointerstitial disease plays an important role in the pathophysiology of diabetic kidney disease. To determine whether biomarkers of tubular injury could predict renal outcome and mortality in patients with type 2 diabetes, we measured urinary levels of kidney injury molecule-1 (KIM-1) and glycoprotein non-metastatic melanoma B (Gpnmb), both normalized to the urinary creatinine, in 978 individuals from the Edinburgh Type 2 Diabetes Study. At baseline, 238 patients had an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 while 147 and 15 patients had microalbuminuria or overt proteinuria, respectively. Both the urine KIM-1 and Gpnmb to creatinine ratios correlated with the urinary albumin to creatinine ratio, the duration of diabetes, and the stringency of glycemic control but not with blood pressure or baseline eGFR. Higher ratios of each marker were associated with a faster decline in kidney function during 4 years of follow-up; however, this was not independent of the urinary albumin to creatinine ratio. Higher KIM-1, but not Gpnmb ratios were associated with an increased risk of mortality, but this association was no longer significant after adjustment for other risk factors, in particular albuminuria. Thus, tubular injury in persons with type 2 diabetes may contribute to the decline in kidney function; however, measuring the urinary concentration of these two tubular biomarkers does not confer additional prognostic information beyond established risk factors.
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http://dx.doi.org/10.1038/ki.2012.218DOI Listing
October 2012

Hyperglycemia and renin-dependent hypertension synergize to model diabetic nephropathy.

J Am Soc Nephrol 2012 Mar 22;23(3):405-11. Epub 2011 Dec 22.

MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.

Rodent models exhibit only the earliest features of human diabetic nephropathy, which limits our ability to investigate new therapies. Hypertension is a prerequisite for advanced diabetic nephropathy in humans, so its rarity in typical rodent models may partly explain their resistance to nephropathy. Here, we used the Cyp1a1mRen2 rat, in which the murine renin-2 gene is incorporated under the Cytochrome P4501a1 promoter. In this transgenic strain, administration of low-dose dietary indole-3-carbinol induces moderate hypertension. In the absence of hypertension, streptozotocin-induced diabetes resulted in a 14-fold increase in albuminuria but only mild changes in histology and gene expression despite 28 weeks of marked hyperglycemia. In the presence of induced hypertension, hyperglycemia resulted in a 500-fold increase in albuminuria, marked glomerulosclerosis and tubulointerstitial fibrosis, and induction of many of the same pathways that are upregulated in the tubulointerstitium in human diabetic nephropathy. In conclusion, although induction of diabetes alone in rodents has limited utility to model human diabetic nephropathy, renin-dependent hypertension and hyperglycemia synergize to recapitulate many of the clinical, histological, and gene expression changes observed in humans.
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http://dx.doi.org/10.1681/ASN.2011060577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294297PMC
March 2012

Association between haptoglobin gene variants and diabetic nephropathy: haptoglobin polymorphism in nephropathy susceptibility.

Nephron Exp Nephrol 2007 12;105(3):e75-9. Epub 2007 Jan 12.

Nephrology Research Group, Queen's University Belfast, Belfast, UK.

Background/aims: The Hp(1)/Hp(2) DNA polymorphism has previously been implicated in susceptibility to diabetic nephropathy in some but not all studies. In an attempt to clarify these conflicting findings, we conducted a case-control association study in a Caucasian population.

Methods: We recruited 224 and 285 type 1 diabetic patients with (cases) and without (controls) nephropathy, respectively, from 2 centres based in Northern Ireland and the Republic of Ireland. Hp(1)/Hp(2) genotyping was performed using a combination of long-range and multiplex PCR. Allele and genotype frequencies in cases and controls were compared using the chi(2) test.

Results: There was a statistically significant increase in the frequency of the Hp(2) allele in cases compared to controls (65.6 vs. 58.6%, OR = 1.35, 95% CI: 1.04-1.76, p = 0.03). The distributions of genotypes were in Hardy-Weinberg equilibrium for both cases and controls, and the overall frequency of the Hp(1) allele was 38.3%, which is similar to that found in other Western European populations.

Conclusions: The results suggest that the Hp(2) allele may confer susceptibility to nephropathy in patients with type 1 diabetes.
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http://dx.doi.org/10.1159/000098563DOI Listing
February 2007

Identifying genes for diabetic nephropathy--current difficulties and future directions.

Nephrol Dial Transplant 2006 Nov 18;21(11):3012-7. Epub 2006 Aug 18.

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http://dx.doi.org/10.1093/ndt/gfl452DOI Listing
November 2006

Role of alpha-adducin DNA polymorphisms in the genetic predisposition to diabetic nephropathy.

Nephrol Dial Transplant 2004 Aug 8;19(8):2019-24. Epub 2004 Jun 8.

Nephrology Research Group, Queen's University of Belfast, Northern Ireland.

Background: There is substantial evidence for genetic susceptibility to diabetic nephropathy. In particular, genes that predispose to hypertension in the general population may confer susceptibility to nephropathy in patients with diabetes. A Gly460Trp variant in the alpha-adducin gene has been associated with essential hypertension. Our aim was to screen the alpha-adducin gene for polymorphisms and to determine if any variants predisposed patients with diabetes to nephropathy. A secondary objective was to assess for association between the Gly460Trp variant and hypertension.

Methods: The exons of the alpha-adducin gene were resequenced in 30 individuals. Selected variants were then genotyped in 155 patients with type 1 diabetes and nephropathy (cases) and 216 persons with type 1 diabetes but no evidence of nephropathy (controls) from Northern Ireland and in 95 cases and 118 controls from the Irish Republic.

Results: Eleven polymorphisms were detected, of which six were novel and three caused amino-acid substitutions. The Gly460Trp and a novel Ser617Cys polymorphism were in strong linkage disequilibrium (D' = 0.98). Neither the genotype nor allele frequencies for the Gly460Trp polymorphism (P = 0.89 and 0.93 respectively) or the Ser617Cys polymorphism (P = 0.46 and 0.76) were significantly different between cases and controls when the Northern Ireland and Irish Republic sample groups were combined. Carriage of the 460Trp allele was not significantly associated with systolic or diastolic blood pressure in either the cases (P = 0.48 and 0.06, respectively) or in the controls (P = 0.50 and 0.94, respectively).

Conclusions: Variation in the alpha-adducin gene does not play a major role in the development of nephropathy in persons with type 1 diabetes in the Irish population. Furthermore, the Gly460Trp variant was not associated with hypertension in this population.
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http://dx.doi.org/10.1093/ndt/gfh342DOI Listing
August 2004

Association between variation in the actin-binding gene caldesmon and diabetic nephropathy in type 1 diabetes.

Diabetes 2004 Apr;53(4):1162-5

Department of Nephrology, Queen's University Belfast, Belfast, Northern Ireland.

Dysfunction of the actin cytoskeleton is a key event in the pathogenesis of diabetic nephropathy. We previously reported that certain cytoskeletal genes are upregulated in mesangial cells exposed to a high extracellular glucose concentration. One such gene, caldesmon, lies on chromosome 7q35, a region linked to nephropathy in family studies, making it a candidate susceptibility gene for diabetic nephropathy. We screened all exons, untranslated regions, and a 5-kb region upstream of the gene for variation using denaturing high-performance liquid chromatography technology. An A>G single nucleotide polymorphism (SNP) at position -579 in the promoter region was associated with nephropathy in a case-control study using 393 type 1 diabetic patients from Northern Ireland (odds ratio [OR] 1.38, 95% CI 1.02-1.86, P = 0.03). A similar trend was found in an independent sample from a second center. When the sample groups were combined (n = 606), the association between the -579G allele and nephropathy remained significant (OR 1.35, 1.07-1.70, P = 0.01). The haplotype structure in the surrounding 7-kb region was determined. No single haplotype was more strongly associated with nephropathy than the -579A>G SNP. These results suggest a role for the caldesmon gene in susceptibility to diabetic nephropathy in type 1 diabetes.
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http://dx.doi.org/10.2337/diabetes.53.4.1162DOI Listing
April 2004