Abrogation of MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damage
Authors: Ghulam Mohammad
Qing Zhong
Julia M dos Santos
Renu A Kowluru
Journal: Diabetes (2011)
Discipline: CLINICAL MEDICINE
Keywords: Diabetic retinopathy; Mitochondrial dysfunction; MMP-9; Apoptosis; Retinal capillary cells
Affiliations: Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA. 

Abstract:  Objective: In the development of diabetic retinopathy, mitochondrial dysfunction is considered to play an important role in the apoptosis of retinal capillary cells. Diabetes activates matrix metalloproteinase-9 (MMP-9) in the retina and its capillary cells, and activated MMP-9 becomes proapoptotic. The objective of this study is to elucidate the plausible mechanism by which active MMP-9 contributes to the mitochondrial dysfunction in the retina. Research design and methods: Using MMP-9 gene knockout (MMP-KO) mice, we investigated the effect of MMP-9 regulation on diabetes-induced increased retinal capillary cell apoptosis, development of retinopathy, mitochondrial dysfunction and ultrastructure, and mitochondrial DNA (mtDNA) damage. To understand how diabetes increases mitochondrial accumulation of MMP-9, interactions between MMP-9 and chaperone proteins (heat shock protein [Hsp] 70 and Hsp60) were evaluated. The results were confirmed in the retinal mitochondria from human donors with diabetic retinopathy, and in isolated retinal endothelial cells transfected with MMP-9 small interfering RNA (siRNA). Results: Retinal microvasculature of MMP-KO mice, diabetic for ‚à? months, did not show increased apoptosis and pathology characteristic of retinopathy. In the same MMP-KO diabetic mice, activation of MMP-9 and dysfunction of the mitochondria were prevented, and electron microscopy of the retinal microvasculature region revealed normal mitochondrial matrix and packed lamellar cristae. Damage to mtDNA was protected, and the binding of MMP-9 with Hsp70 or Hsp60 was also normal. As in the retina from wild-type diabetic mice, activation of mitochondrial MMP-9 and alterations in the binding of MMP-9 with chaperone proteins were also observed in the retina from donors with diabetic retinopathy. In endothelial cells transfected with MMP-9 siRNA, high glucose-induced damage to the mitochondria and the chaperone machinery was ameliorated. Conclusions: Regulation of activated MMP-9 prevents retinal capillary cells from undergoing apoptosis by protecting mitochondrial ultrastructure and function and preventing mtDNA damage. Thus, MMP-9 inhibitors could have potential therapeutic value in preventing the development of diabetic retinopathy by preventing the continuation of the vicious cycle of mitochondrial damage. 

Retracted: No

PubPeer comments:
 Epub 2020 Nov 18  The authors regret an error was made in the generation of Fig. 7A. The image showing MMP-9 staining (red signal) for the 5 mmol L glucose condition was not correct. The corrected figure is shown below and demonstrates an increased localization of MMP-9 in the mitochondria under the 20 mmol L glucose condition compared with cells placed in 5 mmol L glucose. This finding is supported by increased MMP-9 activity in the mitochondria of retinal endothelial cells in 20 mmol L glucose (Fig. 7B and C), and in the retina of diabetic mice (Fig. 2A and B) and of human donors with diabetic retinopathy (Fig. 6A).  , 
 Two images in Figure 1B appear to overlap. ***  ,