The Increased Transforming Growth Factor-β Signaling Induced by Diabetes Protects Retinal Vessels

Abstract

The roles of transforming growth factor (TGF)-b in extracellular matrix production and vascular remodeling, coupled with increased TGF-b expression and signaling in diabetes, suggest TGF-b as an important contributor to the microangiopathy of diabetic retinopathy and nephropathy. To investigate whether increased TGF-b signaling could be a therapeutic target for preventing retinopathy, we used a pharmacologic approach (SM16, a selective inhibitor of the type 1 TGF-b receptor activin receptorelike kinase 5, orally active) to inhibit the increased, but not the basal, Tgf-b signaling in retinal vessels of diabetic rats. At the level of vascular gene expression, 3.5 months' diabetes induced minimal changes. Diabetes þ SM16 for 3 weeks caused widespread changes in gene expression poised to enhance vascular inflammation, thrombosis, leakage, and wall instability; these changes were not observed in control rats given SM16. The synergy of diabetes and SM16 in altering gene expression was not observed in the lung. At the level of vascular network morphology, 7 months' diabetes induced no detectable changes. Diabetes þ SM16 for 3 weeks caused instead distorted morphology and decreased density. Thus, in diabetes, retinal vessels become dependent on a small increase in TGF-b signaling via activin receptorelike kinase 5 to maintain early integrity. The increased TGF-b signaling may protect against rapid retinopathy progression and should not be a target of inhibitory interventions. (Am J Pathol 2017, 187: 627e638; http://dx

TGF-β concentrations and activity are down-regulated in the aqueous humor of patients with neovascular age-related macular degeneration

“…Controversy still exists regarding the role of the TGF-β family members in choroidal neovascularization (CNV), since they have a pleiotropic effect and may play different roles in the regulation of vascular endothelial and smooth muscle cells, being either anti- or pro-angiogenic in a context-dependent way 4 , 5 . In the eye, TGF-β has been shown to act as an anti-angiogenic factor 6 and to protect retinal pigment epithelium (RPE) cells and retinal vasculature 7 – 10 . However, other findings suggest it has a pro-angiogenic effect in the eye: TGF-β not only induces VEGF-A expression by RPE 11 , but its direct and indirect inhibition has also been linked to the inhibition of both the epithelial-mesenchymal transition and senescence of RPE cells in vitro 12 – 15 , as well as to the blockage of CNV 16 – 18 , including the subretinal fibrosis stage 19 , 20 , in animal models.…”

A Pathogenic Mechanism Potentially Operative in Multiple Progressive Diseases and Its Therapeutic Implications

“…Moreover, intracellular angiotensin II signaling has recently been shown to be upregulated in cardiac fibroblasts derived from a canine model of congestive heart failure, and intracellular, but not extracellular, angiotensin II increases collagen‐1 gene expression and collagen secretion in cardiac fibroblasts, again pointing to the importance of intracellular blockade. The potential need for noncanonical intracellular blockade is suggested by the inability of intracellular AT1R blockade to inhibit all intracellular angiotensin II actions . Potentially useful therapeutic approaches in systolic heart failure, chronic renal disease, and AMD include the use of extracellular and intracellular inhibitors of the RAS and TGF‐β as well as mineralocorticoid receptor antagonists and possibly inhibitors of Wnt/β‐catenin signaling .…”

“…The potential need for noncanonical intracellular blockade is suggested by the inability of intracellular AT1R blockade to inhibit all intracellular angiotensin II actions . Potentially useful therapeutic approaches in systolic heart failure, chronic renal disease, and AMD include the use of extracellular and intracellular inhibitors of the RAS and TGF‐β as well as mineralocorticoid receptor antagonists and possibly inhibitors of Wnt/β‐catenin signaling . It should be noted, however, that evidence exists to suggest that some elevation of TGF‐β in diseases such as diabetic retinopathy, as opposed to diabetic nephropathy, may actually be protective by supporting vasculature integrity, indicating that more work needs to be done to determine the appropriate degree and duration of positive loop inhibition in various disorders and tissues; whether any such protective action depends on intracellular, as opposed to canonical extracellular, TGF‐β action should also be determined because blocking 1 (intracellular action, for example) but not another mode of action (conical extracellular signaling) could inhibit pathogenic feedforward loops while maintaining any protective action .…”

Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review

“…In recent times, isoforms of TGF have been studied closely for its downstream effects on certain microRNA (miRNAs) species [202]. It has also been reported that extreme glucose levels may possibly upsurge transcription of TGF-β genes which in turn promotes the elevation levels of TGF-β and its downstream signalling [203][204][205]. Although the mode by which TGF-β activation causes heart problems in diabetic subjects is vague, its activation in such subjects could result from the modulation of the expression of certain changes in miRNAs.…”