Effects of p38 MAPK Inhibition on Early Stages of Diabetic Retinopathy and Sensory Nerve Function

Du, Yunpeng; Tang, Jie; Li, Guangyuan; Berti‐Mattera, Liliana N.; Lee, Chieh Allen; Bartkowski, Darian M.; Gale, David C.; Monahan, Joe; Niesman, Michael R.; Alton, Gordon; Kern, Timothy S.

doi:10.1167/iovs.09-3674

Cited by 105 publications

(81 citation statements)

References 51 publications

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“…At variance with the increased activity reported in the whole retina of diabetic rats, 19 in the isolated retinal vessels, p38/Sapk2a activity was not increased by diabetes, and was not affected by SM16 ( Figure 4A). Finally, it was important to ascertain whether the effects of SM16 could be attributed to inhibition of Alk5 signaling, as opposed to altered Alk1 signaling consequent to diabetes and Alk5 inhibition.…”

Section: Dose Timing and Selectivity Of Sm16 To Prevent Increased Tcontrasting

confidence: 55%

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

Dagher

Gerhardinger

Vaz

et al. 2017

The American Journal of Pathology

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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

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Section: Dose Timing and Selectivity Of Sm16 To Prevent Increased Tcontrasting

confidence: 55%

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

Dagher

Gerhardinger

Vaz

et al. 2017

The American Journal of Pathology

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“…Superoxide levels were measured chemically with lucigenin (bis-N-methylacridinium nitrate), as reported previously (6,11,16,48,49). Immunoblots.…”

Section: Methodsmentioning

confidence: 99%

“…Diabetic (D; 2-mo duration) and age-matched nondiabetic (N) mice (C57BL/6) were killed at 1:00 PM (daylight; 7 h after lights came on) and 1:00 AM (darkness; 7 h after onset of darkness), and superoxide generated in whole retinas was quantitated by reaction with lucigenin (11,16). Sample collection and assays for the darkness data point were carried out in darkness under a dim red light.…”

Section: Significancementioning

confidence: 99%

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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280

285

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Accumulating evidence suggests that photoreceptor cells play a previously unappreciated role in the development of early stages of diabetic retinopathy, but the mechanism by which this occurs is not clear. Inhibition of oxidative stress is known to inhibit the vascular lesions of early diabetic retinopathy, and we investigated whether the diabetes-induced oxidative stress in the retina emanates from photoreceptors. Superoxide generation was assessed in retinas of male C57BL/6J mice made diabetic for 2 mo (4 mo of age when killed) using histochemical (dichlorofluorescein and dihydroethidine) and bioluminescence (lucigenin) methods. Photoreceptors were eliminated in vivo by genetic (opsin −/− ) and chemical (iodoacetic acid) techniques. Immunoblots were used to measure expression of intercellular adhesion molecule 1 and the inducible form of nitric oxide synthase. Diabetes increased the generation of superoxide by diabetic mouse retina more at night than during the day. Photoreceptors were the major source of reactive oxygen species in the retina, and their deletion (either genetically in opsin −/− mice or acutely with iodoacetic acid) inhibited the expected diabetes-induced increase in superoxide and inflammatory proteins in the remaining retina. Both mitochondria and NADPH oxidase contributed to the observed retinal superoxide generation, which could be inhibited in vivo with either methylene blue or apocynin. Photoreceptors are the major source of superoxide generated by retinas of diabetic mice. Pharmaceuticals targeting photoreceptor oxidative stress could offer a unique therapy for diabetic retinopathy.T he pathogenesis of diabetic retinopathy remains unclear, but prior work by us and others has provided strong evidence in animal models that oxidative stress and inflammatory processes play important roles in the development of the vascular lesions characteristic of early stages of this retinopathy (1, 2). Inhibition of oxidative stress by feeding antioxidants or overexpressing antioxidant enzymes has reduced diabetes-induced degeneration of retinal capillaries (3-7). Moreover, oxidative stress has been reported to regulate expression of proinflammatory proteins (8-10), which also have been shown to play a critical role in the pathogenesis of this early retinopathy (2). However, which cells of the retina are the major sources of such oxidative stress in diabetes is unclear. In vitro studies of retinal endothelial cells or Müller cells incubated in elevated levels of glucose have demonstrated that these cells can contribute to oxidative stress (11, 12), but the contribution of other cell types and their relative importance has not been studied.Rod and cone photoreceptor cells are the most prevalent cells in the retina. These postmitotic cells have a very high metabolic rate, using more oxygen than other cells throughout the body. They are also considered as likely contributors to the eventual development of retinal hypoxia and subsequent neovascularization in advanced stages of diabetic retinopathy (13,14). Th...

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“…46 Pharmacological inhibition of the p38 MAPK pathway significantly inhibited diabetes-induced increases of several lesions characteristic of DR, such as acellular capillaries, pericyte ghosts, and adherent leukocytes in the retinal vasculature. 47 Inhibition also reduced levels of proinflammatory mediators, such as intracellular adhesion molecule-1, inducible NO synthase, and superoxides. 47 Therefore, targeting the p38 MAPK pathway may reduce the effects of inflammation in the pathogenesis of DR.…”

Section: Pathways Involved In Retinal Inflammation and Oxidative Strementioning

confidence: 97%

“…47 Inhibition also reduced levels of proinflammatory mediators, such as intracellular adhesion molecule-1, inducible NO synthase, and superoxides. 47 Therefore, targeting the p38 MAPK pathway may reduce the effects of inflammation in the pathogenesis of DR.…”

Section: Pathways Involved In Retinal Inflammation and Oxidative Strementioning

confidence: 97%

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Roy

Kern

Song

et al. 2017

The American Journal of Pathology

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166

147

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Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina. Sustained inflammation induces biochemical and molecular changes, ultimately contributing to retinal complications and vision loss in diabetic retinopathy. In this review, we describe changes involving metabolic abnormalities secondary to hyperglycemia, oxidative stress, and activation of transcription factors, together with neuroglial alterations in the diabetic retina. Changes in biochemical pathways and how they promote pathophysiologic developments involving proinflammatory cytokines, chemokines, and adhesion molecules are discussed. Inflammation-mediated leukostasis, retinal ischemia, and neovascularization and their contribution to pathological and clinical stages leading to vision loss in diabetic retinopathy (DR) are highlighted. In addition, potential treatment strategies involving fibrates, connexins, neuroprotectants, photobiomodulation, and anti-inflammatory agents against the development and progression of DR lesions are reviewed. The importance of appropriate animal models for testing novel strategies against DR lesions is discussed; in particular, a novel nonhuman primate model of DR and the suitability of rodent models are weighed. The purpose of this review is to highlight our current understanding of the pathogenesis of DR and to summarize recent advances using novel approaches or targets to investigate and inhibit the retinopathy. (Am J Pathol 2017, 187: 9e19; http://dx

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Effects of p38 MAPK Inhibition on Early Stages of Diabetic Retinopathy and Sensory Nerve Function

Cited by 105 publications

References 51 publications

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

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

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Mechanistic Insights into Pathological Changes in the Diabetic Retina

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