Protective effect of clusterin on rod photoreceptor in rat model of retinitis pigmentosa

Abstract

Retinitis Pigmentosa (RP) begins with the death of rod photoreceptors and is slowly followed by a gradual loss of cones and a rearrangement of the remaining retinal neurons. Clusterin is a chaperone protein that protects cells and is involved in various pathophysiological stresses, including retinal degeneration. Using a well-established transgenic rat model of RP (rhodopsin S334ter), we investigated the effects of clusterin on rod photoreceptor survival. To investigate the role of clusterin in S334ter-line3 retinas, Voronoi analysis and immunohistochemistry were used to evaluate the geometry of rod distribution. Additionally, immunoblot analysis, Bax activation, STAT3 and Akt phosphorylation were used to evaluate the pathway involved in rod cell protection. In this study, clusterin (10μg/ml) intravitreal treatment produced robust preservation of rod photoreceptors in S334ter-line3 retina. The mean number of rods in 1mm2 was significantly greater in clusterin injected RP retinas (postnatal (P) 30, P45, P60, & P75) than in age-matched saline injected RP retinas (P<0.01). Clusterin activated Akt, STAT3 and significantly reduced Bax activity; in addition to inducing phosphorylated STAT3 in Müller cells, which suggests it may indirectly acts on photoreceptors. Thus, clusterin treatment may interferes with mechanisms leading to rod death by suppressing cell death through activation of Akt and STAT3, followed by Bax suppression. Novel insights into the pathway of how clusterin promotes the rod cell survival suggest this treatment may be a potential therapeutic strategy to slow progression of vision loss in human RP.

Tissue inhibitor of metalloproteinases 1 enhances rod survival in the rd1 mouse retina

“…In rd1 retinas, entire rhodopsin and M-opsin immunoreactive rods and cones are labeled, respectively. The mislocalization of rhodopsin and cone opsins in rd1 was consistent with previous studies [ 58 , 114 – 118 ]. The redistributed rhodopsin and cone opsins may still hold photon perception mechanisms, but their efficiency of signal transference to post-synaptic neurons may be affected, leading to lower ERG responses.…”

Extracellular vesicles released by human retinal pigment epithelium mediate increased polarised secretion of drusen proteins in response to AMD stressors

“…We postulate that, RPE increased release of drusen proteins via EVs in response to AMD stressors such as chronic oxidative stress may initially represent a protective mechanism, since proteins found in drusen are known to play important roles as anti‐angiogenic (Browning et al., 1994 ), anti‐inflammatory (Kelly et al., 1994 ; Mclaughlin et al., 2000 , Wasmuth et al., 2009 ) and anti‐oxidative factors (Kim et al., 2010 ; Tangirala et al., 2001 ), as well as neuroprotective of RPE and photoreceptor cells (Vargas et al., 2017 ). In turn, excessive production and secretion of these proteins, would lead to the spread of the toxic forms of proteins (Alvarez‐Erviti et al., 2011 ; Sardar Sinha et al., 2018 ), propagation of RPE disfunction (Anderson et al., 2002 ; Datta et al., 2017 ; Sakaguchi et al., 2002 ), and formation of drusen deposits (Anderson et al., 2004 ; Bergen et al., 2019 ; Hageman et al., 1999 ; Sakaguchi et al., 2002 ).…”

The antidiabetic drug glibenclamide exerts direct retinal neuroprotection

“…46 Clu encoding clusterin was recently shown to protect against retinal cell death in model of retinitis pigmentosa through activation of Akt and STAT3, followed by Bax suppression. 47 Interestingly, clusterin exerted protective effects in a rodent model of diabetic retinopathy induced by STZ, in which it improved both the retinal barriers and the ERG function. 48 Lcn2, which encodes lipocalin 2, is involved in prosurvival responses during retinal cell stress, increasing immune response gene expression such as Ccl8, Ccl2, and Cxcl10 and anti-oxidant molecules such as hemeoxygenase 1 and superoxide dismutase 2 49 that were all up-regulated by glibenclamide.…”