Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (7): 1570-1577.doi: 10.4103/1673-5374.360277

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L- and T-type Ca2+ channels dichotomously contribute to retinal ganglion cell injury in experimental glaucoma

Hong-Ning Wang1, Wen-Jing Qian1, Guo-Li Zhao1, Fang Li1, Yan-Ying Miao1, Bo Lei2, Xing-Huai Sun3, *, Zhong-Feng Wang1, *   

  1. 1State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China; 2Institutes of Neuroscience and Third Affiliated Hospital, Henan Provincial People’s Hospital, Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China; 3Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, NHC Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Zhong-Feng Wang, PhD, zfwang@fudan.edu.cn; Xing-Huai Sun, PhD, MD, xhsun@shmu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 31872765 and 81790642 (to ZFW), a grant from the Shanghai Municipal Science and Technology Major Project, No. 2018SHZDZX01 (to ZFW), ZJ Lab, and Shanghai Center for Brain Science and Brain-Inspired Technology.

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Abstract:

Retinal ganglion cell apoptotic death is the main pathological characteristic of glaucoma, which is the leading cause of irreversible blindness. Disruption of Ca2+ homeostasis plays an important role in glaucoma. Voltage-gated Ca2+ channel blockers have been shown to improve vision in patients with glaucoma. However, whether and how voltage-gated Ca2+ channels are involved in retinal ganglion cell apoptotic death are largely unknown. In this study, we found that total Ca2+ current densities in retinal ganglion cells were reduced in a rat model of chronic ocular hypertension experimental glaucoma, as determined by whole-cell patch-clamp electrophysiological recordings. Further analysis showed that L-type Ca2+ currents were downregulated while T-type Ca2+ currents were upregulated at the later stage of glaucoma. Western blot assay and immunofluorescence experiments confirmed that expression of the CaV1.2 subunit of L-type Ca2+ channels was reduced and expression of the CaV3.3 subunit of T-type Ca2+ channels was increased in retinas of the chronic ocular hypertension model. Soluble tumor necrosis factor-α, an important inflammatory factor, inhibited the L-type Ca2+ current of isolated retinal ganglion cells from control rats and enhanced the T-type Ca2+ current. These changes were blocked by the tumor necrosis factor-α inhibitor XPro1595, indicating that both types of Ca2+ currents may be mediated by soluble tumor necrosis factor-α. The intracellular mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and nuclear factor kappa-B signaling pathway mediate the effects of tumor necrosis factor-α. TUNEL assays revealed that mibefradil, a T-type calcium channel blocker, reduced the number of apoptotic retinal ganglion cells in the rat model of chronic ocular hypertension. These results suggest that T-type Ca2+ channels are involved in disrupted Ca2+ homeostasis and apoptosis of retinal ganglion cells in glaucoma, and application of T-type Ca2+ channel blockers, especially a specific CaV3.3 blocker, may be a potential strategy for the treatment of glaucoma. 

Key words: apoptosis, CaV1.2, CaV3.3, chronic ocular hypertension, extracellular signal-regulated kinase, mitogen-activated protein kinase, nuclear factor-kappa B, patch-clamp, retina, tumor necrosis factor-α