Integrative Biology of Diabetic Retinal Disease: Lessons from Diabetic Kidney Disease

Abstract

Diabetic retinal disease (DRD) remains the most common cause of vision loss in adults of working age. Progress on the development of new therapies for DRD has been limited by the complexity of the human eye, which constrains the utility of traditional research techniques, including animal and tissue culture models-a problem shared by those in the field of kidney disease research. By contrast, significant progress in the study of diabetic kidney disease (DKD) has resulted from the successful employment of systems biology approaches. Systems biology is widely used to comprehensively understand complex human diseases through the unbiased integration of genetic, environmental, and phenotypic aspects of the disease with the functional and structural manifestations of the disease. The application of a systems biology approach to DRD may help to clarify the molecular basis of the disease and its progression. Acquiring this type of information might enable the development of personalized treatment approaches, with the goal of discovering new therapies targeted to an individual's specific DRD pathophysiology and phenotype. Furthermore, recent efforts have revealed shared and distinct pathways and molecular targets of DRD and DKD, highlighting the complex pathophysiology of these diseases and raising the possibility of therapeutics beneficial to both organs. The objective of this review is to survey the current understanding of DRD pathophysiology and to demonstrate the investigative approaches currently applied to DKD that could promote a more thorough understanding of the structure, function, and progression of DRD.

Keywords: clinical aspects of diabetic retinopathy; diabetic kidney disease; diabetic retinal disease; diabetic retinopathy; microangiopathy; neurovascular unit; research in diabetic retinopathy; systems biology; treatment of diabetic retinopathy.

Figure 1

Systems Biology of diabetic retinal disease (DRD) and diabetic kidney disease (DKD): Integration of Multi-Scalar Data. Individual studies examining either diabetic kidney disease (left column) or diabetic retinal disease (right column) are listed based on the different types of data labeled vertically on the left, demonstrating downward multi-scalar integration of data [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Additionally, the methods and physiologic manifestations of the disease are listed as clinical phenotype and physiologic state, respectively.

Figure 2

The parallel processes of diabetic kidney and retinal disease development and progression demonstrate an opportunity to identify early pathomechanisms of DRD. This figure illustrates a key aspect shared by DRD and DKD: As time progresses from onset of diabetes and adaptive measures have failed, progressive disease ensues (from left to right over time). DKD researchers have recently identified molecular pathways active in early DKD (green bars, top left of chart) that are associated with increased risk for disease progression before classic markers such as albuminuria, serum creatinine, or GFR are affected. By striving to characterize better the molecular pathways active in the analogous preclinical period of DRD (green bar, bottom left of chart) that are associated with progression before VEGF has a central role and visual function is impaired, targeted therapies halting or reversing early disease may become possible. The stages of DKD (top row) progress from the hyperfiltration stage to the silent, incipient, overt DKD stages and ultimately to end-stage kidney disease (ESKD). The stages of DRD (bottom row) progress from preclinical diabetic retinopathy to non-proliferative DR, to proliferative DR. Biomarkers including albuminuria (navy line), creatinine (yellow line), and VEGF (green line) help diagnose the stage of the disease and determine the estimated kidney function by GFR (red line). Similarly, a hypothetical visual function (blue line) could potentially be estimated. GFR: Glomerular filtration rate, VEGF: Vascular endothelial growth factor, DR: Diabetic retinopathy, NPDR: Non-proliferative diabetic retinopathy, PDR: Proliferative diabetic retinopathy.

Figure 3

Integrative biology towards personalized medicine. Three main domains of research are depicted and include clinical data, model systems, and systems biology. Within each domain, multiple nodes of scientific research are detailed. For example, the systems biology domain includes genomics, epigenomics, transcriptomics, proteomics, and metabolomics research. The combination of these three domains contributes to integrative knowledge of pathomechanisms of disease, which when applied to both DKD and DRD culminates in personalized medicine.