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      Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus

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          Abstract

          Objective

          To examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D) from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR).

          Design

          Plasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure.

          Results

          Baseline median albumin excretion rate of study participants was 5.0 μg/min, and mean GFR was 128 mL/min/1.73 m 2. After multivariable adjustment, higher plasma concentration of bradykinin (1–8) was associated with greater glomerular volume (partial r = 0.191, P = 0.019) and total filtration surface area (partial r = 0.211, P = 0.010), and higher bradykinin (1–7) and hyp3-bradykinin (1–7) were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively). In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013), and for participants randomized to losartan, higher hyp3-bradykinin (1–8) was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033).

          Conclusions

          Higher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic nephropathy.

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          Most cited references 42

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          Renal and retinal effects of enalapril and losartan in type 1 diabetes.

          Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin system. We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo. Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.) 2009 Massachusetts Medical Society
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            International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences.

            Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.
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              Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes.

              Levels of proinflammatory cytokines associate with risk for developing type 2 diabetes but whether chronic inflammation contributes to the development of diabetic complications, such as ESRD, is unknown. In the 1990s, we recruited 410 patients with type 2 diabetes for studies of diabetic nephropathy and recorded their characteristics at enrollment. During 12 years of follow-up, 59 patients developed ESRD (17 per 1000 patient-years) and 84 patients died without ESRD (24 per 1000 patient-years). Plasma markers of systemic inflammation, endothelial dysfunction, and the TNF pathway were measured in the study entry samples. Of the examined markers, only TNF receptors 1 and 2 (TNFR1 and TNFR2) associated with risk for ESRD. These two markers were highly correlated, but ESRD associated more strongly with TNFR1. The cumulative incidence of ESRD for patients in the highest TNFR1 quartile was 54% after 12 years but only 3% for the other quartiles (P<0.001). In Cox proportional hazard analyses, TNFR1 predicted risk for ESRD even after adjustment for clinical covariates such as urinary albumin excretion. Plasma concentration of TNFR1 outperformed all tested clinical variables with regard to predicting ESRD. Concentrations of TNFRs moderately associated with death unrelated to ESRD. In conclusion, elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria.
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                Author and article information

                Contributors
                Role: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 July 2017
                2017
                : 12
                : 7
                Affiliations
                [1 ] National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States of America
                [2 ] University of Louisville, Louisville, Kentucky, United States of America
                [3 ] University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [4 ] Boston University School of Medicine, Boston, United States of America
                [5 ] National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America
                [6 ] Ohio State University, Columbus, Ohio, United States of America
                [7 ] University of Minnesota, Minneapolis, Minnesota, United States of America
                University of Glasgow, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ¶ Membership of the CKD Biomarkers Consortium is provided in the Acknowledgments.

                Article
                PONE-D-17-15831
                10.1371/journal.pone.0180964
                5507314
                28700653

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                Page count
                Figures: 3, Tables: 3, Pages: 17
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: U01DK85649
                Funded by: funder-id http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: U01DK085673
                Funded by: funder-id http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: U01DK085660
                Funded by: funder-id http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: U01DK085688
                Funded by: funder-id http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: U01DK085651
                Funded by: funder-id http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: U01DK085689
                Funded by: funder-id http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: Intramural Research Program
                This work was supported by the Chronic Kidney Disease Biomarker Consortium funded by National Institute of Diabetes and Digestive and Kidney Diseases U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651 and U01DK085689, and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The National Institute of Diabetes and Digestive and Kidney Diseases had no role in study design, data collection and analysis, or decision to publish. The project officer representing the National Institute of Diabetes and Digestive and Kidney Diseases had a role in the preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Metabolic Disorders
                Diabetes Mellitus
                Research and Analysis Methods
                Imaging Techniques
                Morphometry
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
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                Diagnostic medicine
                Diabetes diagnosis and management
                HbA1c
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                HbA1c
                Medicine and Health Sciences
                Vascular Medicine
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                Anatomy
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                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
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                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Medicine and Health Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Custom metadata
                All relevant data are within the paper and its Supporting Information files. Investigators wishing to have access to more related data need to contact Krista Whitehead ( kristaw@ 123456mail.med.upenn.edu ) from the CKD Biomarkers Consortium for data access.

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