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Publications

Journal Article Ppublish

PubMed: 39873650 DOI: 10.1167/iovs.66.1.63

CAMK2D and Complement Factor I-Involved Calcium/Calmodulin Signaling Modulates Sodium Iodate-Induced Mouse Retinal Degeneration.

Invest Ophthalmol Vis Sci 66(1):63

Authors: Weixing Xu, Liu Cao, Hua Liu

Affiliations

  • Henan Eye Hospital, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou City, China. School of Graduate, Dalian Medical University, Dalian City, China. Key Laboratory of Age-related Macular Degeneration of Liaoning Province, Jinzhou Medical University, Jinzhou City, China.
  • Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang City, China.
  • School of Graduate, Dalian Medical University, Dalian City, China. Key Laboratory of Age-related Macular Degeneration of Liaoning Province, Jinzhou Medical University, Jinzhou City, China.

Abstract

Purpose

To investigate the effect of Ca2+/calmodulin-dependent protein kinase II (CAMKII) δ subtypes (CAMK2D) on sodium iodate (NaIO3)-induced retinal degeneration in mice.

Methods

Bioinformatics 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.

Results

Bioinformatics 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.

Conclusions

CAMK2D can attenuate the retinal degeneration induced by NaIO3, which was achieved by regulating the CFI.

MeSH

Macular Degeneration, Cells, Genes, Complement Factor I, Calmodulin, Retinal Degeneration, Ophthalmology, Retina, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Retinal Pigments, Fibrinogen, Calcium, Viruses, Tomography, Optical Coherence, Complement System Proteins, Apoptosis, Retinaldehyde