The kallikrein kinin system alters neuroretinal and visual responses in mice

Allen Clermont; Nivetha Murugesan; Cheng-Mao Lin; David Antonetti; Lloyd P Aiello; Edward P Feener

doi:10.1016/j.exer.2025.110484

The kallikrein kinin system alters neuroretinal and visual responses in mice

Exp Eye Res. 2025 Jun 10:258:110484. doi: 10.1016/j.exer.2025.110484. Online ahead of print.

Authors

Allen Clermont¹, Nivetha Murugesan², Cheng-Mao Lin³, David Antonetti⁴, Lloyd P Aiello⁵, Edward P Feener²

Affiliations

¹ KalVista Pharmaceuticals Inc, Cambridge, MA, USA. Electronic address: ACC@Kalvista.com.
² KalVista Pharmaceuticals Inc, Cambridge, MA, USA.
³ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Beetham Eye Institute, Joslin Diabetes Center, Boston, MA, USA.

PMID: 40505713
DOI: 10.1016/j.exer.2025.110484

Abstract

The kallikrein-kinin system (KKS) has been implicated in mediating both VEGF-dependent and VEGF-independent retinal vascular dysfunction and edema; however, little is known about the effect of the KKS on neuroretinal function. This study investigates the effects of bradykinin (BK) and Factor XIIa (FXIIa), an activator of the KKS, on visual function in mice. Intravitreal injection (IVI) of BK decreased optokinetic spatial frequency by 23 %, 20 % and 14 % (p < 0.001) at 6, 12 and 24 h, respectively. IVI of BK increased scotopic electroretinogram (ERG) a-wave amplitudes by 38 % and b-wave by 40 % (p < 0.01) measured at 24 h post injection. IVI of FXIIa increased scotopic ERG a- and b-wave amplitudes by 44 % and 51 % at 24 h post injection. IVI of VEGF increased scotopic a-wave and b-wave amplitudes by 67 % and 71 % (p < 0.001) compared to PBS in wild type (WT) but did not significantly alter the scotopic ERG responses in FXII deficient (FXII^-/-) mice. Pretreatment of WT mice with an oral FXIIa inhibitor, KV998086, reduced the VEGF-induced increase in a-wave amplitude by 99 % (p < 0.001) and b-wave by 90 % (p < 0.01). In summary, this study demonstrates that the KKS alters neuroretinal and visual response in mice. FXIIa inhibition may protect from VEGF-induced visual dysfunction that is mediated by the KKS.

Keywords: Bradykinin; Diabetic macular edema; Electroretinography; FXIIa inhibitor; Factor XII; Kallikrein-kinin system; Vascular endothelial growth factor; Visual dysfunction.