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Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina.

ABSTRACT: Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) atrophy to understand the underlying pathology. RNA sequencing (RNA-seq), qRT-PCR, Western blot, immunohistochemistry of the retinas and multiplex ELISA of the mouse serum were applied to find the pathways involved in the degeneration. NaIO3 caused patchy RPE loss and thinning of the photoreceptor layer. This was accompanied by the increased retinal expression of complement components c1s, c3, c4, cfb and cfh. C1s, C3, CFH and CFB were complement proteins, with enhanced deposition at day 3. C4 was upregulated in retinal degeneration at day 10. Consistently, the transcript levels of proinflammatory ccl-2, -3, -5, il-1β, il-33 and tgf-β were increased in the retinas of NaIO3 mice, but vegf-a mRNA was reduced. Macrophages, microglia and gliotic Müller cells could be a cellular source for local retinal inflammatory changes in the NaIO3 retina. Systemic complement and cytokines/chemokines remained unaltered in this model of NaIO3-dependent retinal degeneration. In conclusion, systemically administered NaIO3 promotes degenerative and inflammatory processes in the retina, which can mimic the hallmarks of geographic atrophy.

SUBMITTER: Enzbrenner A

PROVIDER: S-EPMC8431125 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina.

Enzbrenner Anne A Zulliger Rahel R Biber Josef J Pousa Ana Maria Quintela AMQ Schäfer Nicole N Stucki Corinne C Giroud Nicolas N Berrera Marco M Kortvely Elod E Schmucki Roland R Badi Laura L Grosche Antje A Pauly Diana D Enzmann Volker V

International journal of molecular sciences 20210826 17

Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO<sub>3</sub>)-induced retinal pigment epithelium (RPE) atrophy to understand the ...[more]

PMID: 34502128

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Project description:BackgroundSodium iodate (SI) is a chemical widely applied to induce retina degeneration in animal models. SI treatment caused formation of rosettes/folds in the outer nuclear layer (ONL) of the rat retina, but it was previously unclear whether SI also forms rosettes in mice. In addition, SI induced retina degeneration was never addressed in non-separate sclerochoroid/retina pigment epithelium/retina whole mount. Here we displayed features of retina degeneration including rosette formation in mice and developed a morphological analytic assessment using sclerochoroid/retina pigment epithelium/retina whole mounts.MethodsSI was intraperitoneally injected in Sprague-Dawley (SD) rats and C57BL/6J mice using a single dose (50 mg/kg) or with a dose range (10 to 50 mg/kg) in BALB/C mice. Rat retinas were investigated up to 2-week post-injection by histology and whole mounts, and mouse retinas were investigated up to 3-week post-injection by histology, fluorescent staining of sections and/or sclerochoroid/retina pigment epithelium/retina whole mounts for the morphological evaluations of the SI-induced retina damage.ResultsSI-induced retina damage caused photoreceptor (PR) degeneration and rosettes/folds formation, as well as retina pigment epithelium degeneration and inward migration. It displayed mixed nuclei from choroid to PRs, due to layer disorganization, as shown by single horizontal images in the sclerochoroid/retina pigment epithelium/retina whole mounts. Measurement of the PR rosette area induced by SI provided a quantitative, morphological evaluation of retina degeneration.ConclusionsThe method of non-separate sclerochoroid/retina pigment epithelium/retina whole staining and mount allows us to observe the integral horizontal view of damage from sclera to PR layers, which cannot be addressed by using sectioned and separate whole mount methods. This method is applicable for morphological evaluation of retina damage, especially in the subretinal layer.

Project description:PurposeTo investigate the effect of Ca2+/calmodulin-dependent protein kinase II (CAMKII) δ subtypes (CAMK2D) on sodium iodate (NaIO3)-induced retinal degeneration in mice.MethodsBioinformatics analysis and Western blot experiments were used to screen the significantly differentially expressed genes in age-related macular degeneration (AMD) disease. CAMK2D knockdown and overexpression models were constructed by lentivirus (LV) infection of adult retinal pigment epithelial cell line-19 (ARPE-19) cells in vitro. Flow cytometry was used to detect ARPE-19 cell apoptosis induced by NaIO3. In vivo, CAMK2D knockdown and overexpression mouse models were generated by infecting mouse retinal pigment epithelium (RPE) with adeno-associated virus (AAV). Retinography, optical coherence tomography (OCT), and histological analysis (hematoxylin and eosin staining) were used to detect NaIO3-induced retinal structural changes in mice. Electroretinography (ERG) was used to detect NaIO3-induced retinal function changes in mice. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the apoptosis of retinal cells induced by NaIO3. RNA sequencing (RNA-Seq) and bioinformatics analysis were used to screen for target genes affected by CAMK2D in CAMK2D-overexpressing ARPE-19 cells. And flow cytometry, OCT, and ERG were used to evaluate the regulatory effect of CAMK2D on target genes.ResultsBioinformatics analysis found the expression of genes related to Ca2+ signal was significantly reduced in AMD patients. Western blot showed that in a mouse model of dry AMD induced by NaIO3, CAMK2D expression in RPE-Choroid tissue significantly lower than normal mice. In vitro, our results showed that overexpression of CAMK2D in ARPE-19 cells decreased apoptosis induced by NaIO3 and knockdown increased apoptosis. In vivo, CAMK2D overexpression in RPE cells can attenuate the retina degeneration induced by NaIO3 and CAMK2D knockdown aggravated degeneration. The bioinformatics analysis indicated that CAMK2D might affect AMD pathology through complement factor I (CFI). In vitro, knockdown of CFI in ARPE-19 cells increased apoptosis induced by NaIO3. In knockdown CFI ARPE-19 cells, overexpression of CAMK2D reduced the above apoptosis. In mice retina, CFI knockdown can aggravate the retina degeneration induced by NaIO3. In knockdown CFI mice, overexpression of CAMK2D in RPE can attenuate the above retina degeneration. Western blot confirmed that CAMK2D regulated the expression of CFI in mice.ConclusionsCAMK2D can attenuate the retinal degeneration induced by NaIO3, which was achieved by regulating the CFI.

Dataset Information

Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina.

Publications

Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina.

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