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 40

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Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes.

Monika A Niewczas, Tomohito Gohda, Jan Skupien … (2012)

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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Endothelium-derived relaxing and contracting factors.

R. F. Furchgott, P Vanhoutte (1989)

Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.

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Early Progressive Renal Decline Precedes the Onset of Microalbuminuria and Its Progression to Macroalbuminuria

Andrzej Krolewski, Monika A Niewczas, Jan Skupien … (2013)

OBJECTIVE Progressive decrease in the glomerular filtration rate (GFR), or renal decline, in type 1 diabetes (T1D) is observed in patients with macroalbuminuria. However, it is unknown whether this decline begins during microalbuminuria (MA) or normoalbuminuria (NA). RESEARCH DESIGN AND METHODS The study group (second Joslin Kidney Study) comprises patients with T1D and NA (n = 286) or MA (n = 248) who were followed for 4–10 years (median 8 years). Serial measurements (median 6, range 3–16) of serum creatinine and cystatin C were used jointly to estimate GFR (eGFRcr-cys) and assess its trajectories during follow-up. RESULTS Renal decline (progressive eGFRcr-cys loss of at least 3.3% per year) occurred in 10% of the NA and 35% of the MA (P < 0.001). In both groups, the strongest determinants of renal decline were baseline serum concentrations of uric acid (P < 0.001) and tumor necrosis factor receptor 1 or 2 (TNFR-1 or -2, P < 0.001). Other significant risk factors included baseline HbA1c, age/diabetes duration, and systolic blood pressure. Relative impacts of these determinants were similar in NA and MA. Renal decline was not associated with sex or baseline serum concentration of TNF-α, IL-6, IL-8, IP-10, MCP-1, VCAM, ICAM, Fas, or FasL. CONCLUSIONS Renal decline in T1D begins during NA and it is determined by multiple factors, similar to MA. Thus, this early decline is the primary disease process leading to impaired renal function in T1D. Changes in albumin excretion rate, such as the onset of MA or its progression to macroalbuminuria, are either caused by or develop in parallel to the early renal decline.

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Author and article information

Contributors

Kevin M. Wheelock: Role: Formal analysisRole: Writing – original draftRole: Writing – review & editing

Jian Cai: Role: ConceptualizationRole: Data curationRole: InvestigationRole: Writing – review & editing

Helen C. Looker: Role: Formal analysisRole: Writing – original draftRole: Writing – review & editing

Michael L. Merchant: Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing

Robert G. Nelson:

ORCID: http://orcid.org/0000-0001-7307-3786

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

Gudeta D. Fufaa: Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing

E. Jennifer Weil: Role: Writing – review & editing

Harold I. Feldman: Role: Project administrationRole: SupervisionRole: Writing – review & editing

Ramachandran S. Vasan: Role: Project administrationRole: SupervisionRole: Writing – review & editing

Paul L. Kimmel: Role: Funding acquisitionRole: Project administrationRole: ResourcesRole: Writing – review & editing

Brad H. Rovin: Role: ConceptualizationRole: Project administrationRole: ResourcesRole: Writing – review & editing

Michael Mauer: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing

Jon B. Klein: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Harald Mischak: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 10 July 2017

Publication date Collection: 2017

Volume: 12

Issue: 7

Electronic Location Identifier: e0180964

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.

* E-mail: rnelson@ 123456nih.gov

Author information

Robert G. Nelson http://orcid.org/0000-0001-7307-3786

Article

Publisher ID: PONE-D-17-15831

DOI: 10.1371/journal.pone.0180964

PMC ID: 5507314

PubMed ID: 28700653

SO-VID: 832aa89d-2de3-4f65-a3d8-c42d873fc68a

License:

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.

History

Date received : 24 April 2017

Date accepted : 23 June 2017