Emerging Roles of Transforming Growth Factor b Signaling in Diabetic Retinopathy SARAH E. WHEELER 1 AND NAM Y. LEE 1,2,3 * 1 Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 2 Davis Heart Lung Research Institute, The Ohio State University, Columbus, Ohio 3 James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio Diabetic retinopathy (DR) is a serious complication of diabetes mellitus affecting about one third of diabetic adults. Despite its prevalence, treatment options are limited and often implemented only in the later stages of the disease. To date, the pathogenesis of DR has been extensively characterized in the context of elevated glucose, insulin, and VEGF signaling, although a growing number of other growth factors and molecules, including transforming growth factor b (TGF-b) are being recognized as important contributors and/or therapeutic targets. Here, we review the complex roles of TGF-b signaling in DR pathogenesis and progression. J. Cell. Physiol. 9999: 1–4, 2016. ß 2016 Wiley Periodicals, Inc. Diabetic retinopathy (DR) is one of the most serious complications of type 1 and 2 diabetes mellitus and remains a leading cause of blindness worldwide (Pascolini and Mariotti, 2012; Yau et al., 2012). Currently, about one third of adults with diabetes in the United States suffer from DR (Zhang et al., 2010), and by 2030, over 16 million Americans are predicted to be afflicted by this condition (Saaddine et al., 2008). Management of risk factors such as hypertension and hyperglycemia are deemed critical in preventing the onset and progression of the disease, alongside current treatments including photocoagulation, anti- VEGF agents, corticosteroids, or vitreoretinal surgery (Simo and Hernandez, 1995). The pathogenesis of DR has been studied extensively in the context of glucose (The Diabetes Control and Complications Trial, 1995; Stratton et al., 2001; Zhang et al., 2001; Holman et al., 2008), insulin (Bronson et al., 2003; Reiter and Gardner, 2003), and VEGF signaling (Osaadon et al., 2014; Wang et al., 2015), all of which have central roles and therefore have been covered extensively in a number of comprehensive reviews. Nevertheless, there are a growing number of other growth factors and cytokines underlying this complex disorder (Simo et al., 2006; Zorena et al., 2013a). Here, we review the emerging roles of transforming growth factor b (TGF-b) signaling pathways in DR and their potential as therapeutic targets. Pathophysiology of DR DR is a progressive disease classified into two stages: non- proliferative (NPDR) and proliferative (PDR) (Cheung et al., 2010). Roughly 90% of type 1 diabetic patients are affected by DR, with clinical symptoms typically manifesting 5 or more years following the onset of diabetes (Zorena et al., 2013b). Although prolonged hyperglycemia is one of the primary causes of DR (Zorena et al., 2013a), it is becoming increasingly clear that substrate imbalance, ischemia, and other factors contribute to the development of this disease (Frank, 2004; Zorena et al., 2013a). The early signs of DR observed in NPDR are inflammation, leukostasis, and thickening of the basal lamina surrounding the blood vessels and capillaries. This gradual thickening promotes the loss of retinal pericytes and endothelial cells (ECs) and causes breakdown of the blood-retinal barrier to mediate vascular hyperpermeability (Frank, 2004; Kuiper et al., 2007; Walshe et al., 2009; Zhang et al., 2011). These early changes precede initial microangiopathies including the formation of microaneurysms, small outpouchings from retinal capillaries, and dot intraretinal hemorrhages (Frank, 2004; Sapieha et al., 2010; Antonetti et al., 2012). During disease progression, capillary damage and hemorrhages increase in frequency and size. Damage to the retinal capillary barrier can result in deposition of plasma lipids and lipoproteins, eventually occluding the vessels toward ischemia and hypoxia and subsequent apoptosis of nerve cells. Release of growth factors such as VEGF from retinal ECs, pericytes, and pigment epithelial cells occurs in response to hypoxia (Cheung et al., 2010; Braunger et al., 2015). VEGF production allows for uncontrolled neovascularization of retinal capillaries, marking the progression of the disease from NPDR to PDR, and increasing the overall risk of vision loss (Cheung et al., 2010; Braunger et al., 2015). These new capillaries are prone to damage since they tend to be hyperpermeable, fragile, and breach the internal limiting membrane separating the retina from the vitreous, allowing them to extend into the vitreous (Frank, 2004; Hendrick et al., 2015). In end stage PDR, newly formed fibrogenic tissues surrounding the vasculature contract, leading to hemorrhages, retinal detachment, and blindness (Saika et al., 2009; Klaassen et al., 2015). TGF-b Signaling in DR Overview of TGF-b superfamily signaling The TGF-b superfamily consists of over 30 members, including the prototype, TGF-b1, as well as activins, nodals, and bone morphogenetic proteins (BMPs 1–20) (Gordon and Blobe, 2008; Weiss and Attisano, 2013). These ligands have diverse and often context-specific actions including growth-inhibition, differentiation, apoptosis, and migration, and as such, TGF-b pathways have underlying roles in a wide range of disease states *Correspondence to: Prof. Nam Y. Lee, Division of Pharmacology, College of Pharmacy, The Ohio State University, 442 Riffe Building, 496 West 12th Ave, Columbus 43210, OH. E-mail: lee.5064@osu.edu Manuscript Received: 27 July 2016 Manuscript Accepted: 28 July 2016 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015. DOI: 10.1002/jcp.25506 MINI-REVIEW 1 Journal of Journal of Cellular Physiology Cellular Physiology © 2016 WILEY PERIODICALS, INC.