Retinal synthesis and deposition of complement components induced by ocular hypertension

Kuehn, Markus H.; Kim, Chan Yun; Ostojić, Jelena; Bellin, M.; Alward, Wallace L.M.; Stone, Edwin M.; Sakaguchi, Donald S.; Grozdanić, Siniša D.; Kwon, Young H.

doi:10.1016/j.exer.2006.03.002

Cited by 136 publications

(137 citation statements)

References 42 publications

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“…4C). Although this approach relies on continuous expression of this RGC marker, we and others have found a high correlation between RGC numbers and optic nerve damage (24,(29)(30)(31)(32)(33)(34). Data obtained here demonstrate that eyes of vehicle control Tg-MYOC Y437H animals display a significantly lower RGC density than those of WT controls (1706.9 ± 491.3 RGC/mm 2 vs. 2171.9 ± 186.3 RGC/mm 2 , P = 0.027).…”

Section: Resultsmentioning

confidence: 55%

“…However, the anterior segment, including the TM, develops normally in these mice and disturbances in aqueous humor outflow dynamics only become apparent as the animals age. Importantly, similar to human POAG, the pathophysiological events leading to reduced aqueous humor outflow are not associated with gross morphological disruption of the aqueous humor drainage structures, as is the case in many surgically induced models or those resulting from congenital anterior segment malformation (33,43). Thus, we reasoned that the TM in these mice will be amenable to restoration.…”

Section: Discussionmentioning

confidence: 99%

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Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Zhu

Gramlich

Laboissonniere

et al. 2016

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

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133

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Glaucoma is a common cause of vision loss or blindness and reduction of intraocular pressure (IOP) has been proven beneficial in a large fraction of glaucoma patients. The IOP is maintained by the trabecular meshwork (TM) and the elevation of IOP in open-angle glaucoma is associated with dysfunction and loss of the postmitotic cells residing within this tissue. To determine if IOP control can be maintained by replacing lost TM cells, we transplanted TM-like cells derived from induced pluripotent stem cells into the anterior chamber of a transgenic mouse model of glaucoma. Transplantation led to significantly reduced IOP and improved aqueous humor outflow facility, which was sustained for at least 9 wk. The ability to maintain normal IOP engendered survival of retinal ganglion cells, whose loss is ultimately the cause for reduced vision in glaucoma. In vivo and in vitro analyses demonstrated higher TM cellularity in treated mice compared with littermate controls and indicated that this increase is primarily because of a proliferative response of endogenous TM cells. Thus, our study provides in vivo demonstration that regeneration of the glaucomatous TM is possible and points toward novel approaches in the treatment of this disease.G laucoma is one of the most common causes of irreversible vision loss and blindness worldwide; ∼60 million suffer from this disease, and of these, 7 million are blind (1). By definition all glaucoma involves some degree of vision loss, which is because of the death of retinal ganglion cells (RGC), as well as degeneration of the optic nerve head, the optic nerve, and the lateral geniculate nucleus (2, 3). Advanced age and elevated intraocular pressure (IOP) are the two most significant risk factors for the development of glaucoma. Elevated IOP is typically a result of disturbances in the balance of aqueous humor production and drainage. Aqueous humor is continuously synthesized within the eye and drained primarily through the trabecular meshwork (TM), a specialized structure located anterior to the root of the iris. Although occlusion of the aqueous humor outflow pathways can occur through several mechanisms, in the United States and other Western populations the most common form of glaucoma is primary open angle glaucoma (POAG), which manifests no gross abnormalities to the anterior portion of the eye.Randomized clinical trials have shown that reduction of IOP slows the onset and progression of glaucoma, even in patients without suspicious elevation of IOP (4, 5). Although there has been increasing awareness that factors other than elevated IOP contribute to glaucomatous damage, to date all treatments for glaucoma remain aimed at reducing IOP either through surgical or medical means, which has resulted in significant preservation of vision and increased quality of life for millions of glaucoma patients (6, 7).Although the TM in eyes with POAG appears relatively normal at a gross morphological level, a number of more subtle changes influencing the mechanical properties of the TM collage...

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Section: Resultsmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Zhu

Gramlich

Laboissonniere

et al. 2016

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

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133

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“…In a model of ocular hypertension, C1q expression was similarly localized to the nerve fiber layer and the ganglion cell layer (Kuehn et al 2006). Thus, the retina may respond to different types of retinal injury by an up-regulation of the classical complement activation cascade.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the retina may respond to different types of retinal injury by an up-regulation of the classical complement activation cascade. As for glaucoma and the model of ocular hypertension (Kuehn et al 2006;Stasi et al 2006), the classical complement pathway of the innate immune response was found to be upregulated in the rd1 mouse model of photoreceptor apoptosis and retinal degeneration at the mRNA level. In addition, genes of the acquired immune system were induced as well.…”

Section: Introductionmentioning

confidence: 99%

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Rohrer

Demos

Frigg

et al. 2007

Experimental Eye Research

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Misregulation of the innate immune response and other immune-related processes have been suggested to play a critical role in the pathogenesis of a number of different neurodegenerative diseases, including age related macular degeneration. In an animal model for photoreceptor degeneration, several genes of the innate and acquired immune system were found to be differentially regulated in the retina during the degenerative process. In addition to this differential regulation of individual genes, we found that in the rd1 retina a significantly higher number of genes involved in immune-related responses were expressed at any given time during the degenerative period. The peak of immune-related gene expression was at postnatal day 14, coinciding with the peak of photoreceptor apoptosis in the rd1 mouse. We directly tested the potential involvement of acquired and innate immune responses in initiation and progression of photoreceptor degeneration by analyzing double mutant animals. Retinal morphology and photoreceptor apoptosis of rd1 mice on a SCID genetic background (no mature T-and B-cells) or in combination with a RAG-1 (no functional B-and T-cells) or a C1qα (no functional classical complement activation pathway) knockout was followed during the degenerative process using light microscopy or TUNEL staining, respectively. Although complement factor C1qα was highly up-regulated in the rd1 retina concomitantly with the degenerative process, lack of this protein did not protect the rd1 retina. Similarly, retinal degeneration and photoreceptor apoptosis appeared to proceed normally in the rd1 mouse lacking functional Band T-cells. Our results suggest that both, the classical complement system of innate immunity and a functional acquired immune response are not essential for the degenerative process in the rd1 mouse retina.

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“…Иммунной агрессии подвергаются собственные нейроны: ганглиоз-ные клетки сетчатки (ГКС), их синапсы и аксоны [32,34]. Депозиты белков комплемента в сетчат-ке глаз с терминальной глаукомой подтверждают ее участие в патогенезе ПОУГ [17,28]. Система комплемента является неотъемлемой частью врожденного иммунитета и предназначена для очистки от нежелательных клеток, инфекцион-ных агентов и продуктов клеточного распада [37].…”

Section: Sokolov Va Et Al соколов ва и др Medical Immunology (Runclassified

Expression of Matrix Metalloproteinases in Lacrimal Fluid and Gene Polymorphism of Complement Factor H (Cfh) in Patients With Primary Open-Angle Glaucoma

Sokolov¹,

Лихванцева²,

Levanova³

et al. 2017

Med. immunol.

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Резюме. Цель -изучить продукцию матриксных металлопротеиназы-2 и -9 в слезной жидкости и полиморфизм гена СFH в популяции больных первичной открытоугольной глаукомой.Исследование проведено на 120 глазах больных первичной открытоугольной глаукомой (ПОУГ), из них 34 глаза с начальной стадией, 35 глаз -с развитой, 35 -с далекозашедшей стадией и 16 глаз -с терминальной стадией. Контролем служили 25 пациентов без глаукомы. Объектом биохимического исследования служила слезная жидкость. Уровни ММП-2 и ММП-9 определяли «сэндвич»-методом твердофазного иммуноферментного анализа на обоих глазах.Материалом генетического исследования служила венозная кровь. Анализу подвергали геномную ДНК человека, выделенную из лейкоцитов цельной крови. Применяли метод ПЦР.Результаты исследования анализировали с помощью пакета прикладных статистических программ SAS (Statistical Analysis System, SAS Institute Inc., США) с применением стандартных алгоритмов ва-риационной статистики, включая корреляционный анализ и анализ таблиц сопряженности, а так-же различные типы межгруппового сравнения распределений изучаемых показателей. Установлено, что среднегрупповые показатели металлопротеиназ-2 и -9 увеличиваются по мере прогрессирования заболевания. Проведен корреляционный анализ сопряженности связи между морфометрическими, клинико-функциональными параметрами и количественными показателями ММП-2 и ММП-9. Из-учена распространенность полиморфизма гена CFH с учетом стадии развития глаукомы.Исследование представило доказательства взаимосвязи продукции ММП-2 и ММП-9 с полимор-физмом гена СFH, а также расширило список генетических мутаций, принимающих возможное уча-стие в патогенезе ПОУГ. Россия, г. Рязань, ул. 2-я Линия, 3/40.

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Retinal synthesis and deposition of complement components induced by ocular hypertension

Cited by 136 publications

References 42 publications

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Expression of Matrix Metalloproteinases in Lacrimal Fluid and Gene Polymorphism of Complement Factor H (Cfh) in Patients With Primary Open-Angle Glaucoma

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