Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema

Takeshi Kita, Allen C. Clermont, Nivetha Murugesan, Qunfang Zhou, Kimihiko Fujisawa, Tatsuro Ishibashi, Lloyd Paul Aiello, Edward P. Feener

Research output: Contribution to journalArticle

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Abstract

This study characterizes the kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma prekallikrein (PPK) and plasma kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME.

Original languageEnglish
Pages (from-to)3588-3599
Number of pages12
JournalDiabetes
Volume64
Issue number10
DOIs
Publication statusPublished - Oct 2015

Fingerprint

Plasma Kallikrein
Kallikrein-Kinin System
Macular Edema
Vascular Endothelial Growth Factor A
Retinal Vessels
Capillary Permeability
Prekallikrein
Retinal Perforations
Bradykinin Receptors
Vascular Endothelial Growth Factor Receptor-2
Nitric Oxide Synthase Type III
Bradykinin
Nitric Oxide Synthase Type II
Proteomics
Mass Spectrometry
Proteins

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Kita, T., Clermont, A. C., Murugesan, N., Zhou, Q., Fujisawa, K., Ishibashi, T., ... Feener, E. P. (2015). Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema. Diabetes, 64(10), 3588-3599. https://doi.org/10.2337/db15-0317

Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema. / Kita, Takeshi; Clermont, Allen C.; Murugesan, Nivetha; Zhou, Qunfang; Fujisawa, Kimihiko; Ishibashi, Tatsuro; Aiello, Lloyd Paul; Feener, Edward P.

In: Diabetes, Vol. 64, No. 10, 10.2015, p. 3588-3599.

Research output: Contribution to journalArticle

Kita, T, Clermont, AC, Murugesan, N, Zhou, Q, Fujisawa, K, Ishibashi, T, Aiello, LP & Feener, EP 2015, 'Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema', Diabetes, vol. 64, no. 10, pp. 3588-3599. https://doi.org/10.2337/db15-0317
Kita, Takeshi ; Clermont, Allen C. ; Murugesan, Nivetha ; Zhou, Qunfang ; Fujisawa, Kimihiko ; Ishibashi, Tatsuro ; Aiello, Lloyd Paul ; Feener, Edward P. / Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema. In: Diabetes. 2015 ; Vol. 64, No. 10. pp. 3588-3599.
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