Plasma kallikrein-kinin system and diabetic retinopathy

Abstract

Diabetic retinopathy (DR) occurs to some extent in most people with at least 20 years duration of diabetes mellitus. Progression of DR to its sight threatening stages is usually associated with worsening of underlying retinal vascular dysfunction and disease. The plasma kallikrein kinin system (KKS) is activated during vascular injury, where it mediates important functions in innate inflammation, blood flow, and coagulation. Recent findings from human vitreous proteomics and experimental studies on diabetic animal models have implicated the KKS in contributing to DR. Vitreous fluid from people with advanced stages of DR contains increased levels of plasma KKS components, including plasma kallikrein (PK), coagulation Factor XII, and high molecular weight kininogen. Both bradykinin B1 (B1R) and B2 (B2R) receptors isoforms are expressed in human retina, and retinal B1R levels are increased in diabetic rodents. Activation of the intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening, and these responses are exacerbated in diabetic rats. Preclinical studies have shown that administration of PK inhibitors and B1R antagonists to diabetic rats ameliorates retinal vascular hyperpermeability and inflammation. These findings suggest that components of plasma KKS are potential therapeutic targets for diabetic macular edema.

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

“…Anti-VEGF treatment is only partially effective against diabetic macular edema (119), and the identification of additional, VEGF-independent pathogenic molecules in this condition could lead to new treatments that better preserve vision. Additional molecular targets have been identified for pharmacologic inhibition, including TNF-α (120), the plasma kallikrein pathway (121), and lipoprotein-associated phospholipase A2 (Lp-PLA2) (122). Broadening therapeutic objectives beyond direct suppression of pathologic vascular changes may be promising.…”

The progress in understanding and treatment of diabetic retinopathy

“…In this context, inhibitors of the pre-kallikrein-kinin (PKK) pathway have shown promise for DME (Giusti et al, 2001;Liu and Feener, 2013) with an VEGFindependent mode of action (Kita et al, 2012). Importantly, better predictors of treatment response should be sought so that stratified approaches could be implemented.…”

Biomarkers in Diabetic Retinopathy

“…It can be applied to cultured cells, and to plasma, serum, urine, and tissues, including ocular tissues such as the vitreous in animals and humans. Proteomics studies are starting to emerge in the field of diabetic retinopathy [27,28,[307][308][309][310][311][312][313]. Usually, dozens of differentially expressed proteins are identified, but subject numbers are usually small, and confounders such as intraocular blood and clinical factors are often not well considered.…”