NDRG2 alleviates photoreceptor apoptosis by regulating the STAT3/TIMP3/MMP pathway in mice with retinal degenerative disease

Abstract

Photoreceptor apoptosis is the main pathological feature of retinal degenerative diseases; however, the underlying molecular mechanism has not been elucidated. Recent studies have shown that N‐myc downstream regulated gene 2 (NDRG2) exerts a neuroprotective effect on the brain and spinal cord. In addition, our previous studies have confirmed that NDRG2 is expressed in mouse retinal photoreceptors and counteracts N‐methyl‐N‐nitrosourea (MNU)‐induced apoptosis. However, the underlying molecular mechanism remains unclear. In this study, we observed that the expression of NDRG2 was not only significantly inhibited in photoreceptors after MNU treatment but also after hydrogen peroxide treatment, and photoreceptor apoptosis was alleviated or aggravated after overexpression or knockdown of NDRG2 in the 661W photoreceptor cell line, respectively. The apoptosis inhibitor Z‐VAD‐FMK rescued photoreceptor apoptosis induced by MNU after NDRG2 knockdown. Next, we screened and identified tissue inhibitor of metalloproteinases 3 (TIMP3) as the downstream molecule of NDRG2 in 661W cells by using quantitative real‐time polymerase chain reaction. TIMP3 exerts a neuroprotective effect by inhibiting the expression of matrix metalloproteinases (MMPs). Subsequently, we found that signal transducer and activator of transcription 3 (STAT3) mediated the NDRG2‐associated regulation of TIMP3. Finally, we overexpressed NDRG2 in mouse retinal tissues by intravitreally injecting an adeno‐associated virus with mouse NDRG2 in vivo. Results showed that NDRG2 upregulated the expression of phospho‐STAT3 (p‐STAT3) and TIMP3, while suppressing MNU‐induced photoreceptor apoptosis and MMP expression. Our findings revealed how NDRG2 regulates the STAT3/TIMP3/MMP pathway and uncovered the molecular mechanism underlying its neuroprotective effect on mouse retinal photoreceptors.

Posterior Polar Annular Choroidal Dystrophy: Genetic Insights and Differential Diagnosis in Inherited Retinal Diseases

“…Transmembrane protein [48,49] Involved in photoreceptor disk morphogenesis [48,49] 4p15.32 [48,49] TIMP3 Metallopeptidase inhibitor [50] Involved in ocular development [50] 22q12.3 [50] CCD2D2A Binding domain protein [3] Uncertain significance, possibly related to cilia structure and function [3] 4q21.1 [3] CEP78 Centrosomal protein [51] May be involved in ciliary functions [51] 9q21.13 [51] NR2E3 Nuclear receptor [3,21,22,52] Key transcription factor for photoreceptor development [3,21,22,52] 15q23 [21,22] PCARE Ciliary and actin-associated protein [3,23,53] Probably associated with the primary cilium of the outer segment [3,23,53] 2p23.2 [53]…”