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Ghulam Mohammad, Renu A Kowluru; Inhibition of MMP9 Protects the Development of Retinopathy in Diabetic Mice Via Ameliorating Mitochondria Dysfunction. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4447.
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Matrix metalloproteinase proteases (MMPs) induction is considered as a negative regulator of cell survival, and in diabetes, latent MMPs are activated in the retina and its capillary cells, and activation of MMP9 induces apoptosis of retinal capillary cells, a phenomenon that precedes the development of histopathology characteristic of retinopathy. We have shown that mitochondrial dysfunction plays an important role in the development of diabetic retinopathy. The goal of this study is to understand the mechanism via which activation of MMP9 contributes to the development of diabetic retinopathy.
Capillary cell apoptosis was detected by terminal transferase dUTP nick-end labeling (TUNEL), and the number of acellular capillaries was counted in the trypsin digested retinal microvasculature isolated from MMP9 knockout mice (MMP9-KO) and C57BL/6J wild type mice (WT), diabetic (streptozotocin-induced) for 7-8 months. Retinal mitochondria were analyzed for MMP9 activation by quantifying its gelatinase activity and expression. Mitochondria swelling, voltage-dependent anion channel (VDAC) and connexin43 were quantified to evaluate mitochondrial membrane integrity, and the import-export machinery was evaluated by investigating mitochondrial heat shock protein 70 (Hsp70), translocase of the outer membrane 34 (TOM 34) and translocase of the inner membrane 44 (TIM44) by western blotting. Mitochondria dysfunction was examined by quantifying the abundance of Bax and cytochrome c.
Retina from diabetic mice with MMP9 gene silenced had lower number of TUNEL-positive capillary cells and acellular capillaries (8 ± 1 and 5.3 ± 1.4respectively) as compared to those obtained from WT-diabetic mice (13 ± 2 and 10 ± 2 respectively), and these values were comparable to the obtained from MMP9-KO or WT non diabetic mice. Diabetes also failed to have any effect on retinal mitochondrial MMP9 activity in MMP9-KO mice, and mitochondrial integrity, import-export machinery and function were also normal; the values were not significantly different from those obtained from MMP9-KO or WT non diabetic mice.
Regulation of MMP9 activation prevents retinal capillary cells from undergoing apoptosis and the development of retinopathy via protecting mitochondrial integrity and transport machinery. Thus, MMP9 inhibitors, which are being used for other diseases, have potential to inhibit the development of retinopathy in diabetes via protecting mitochondrial integrity.
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