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First published online October 18, 2006
Journal of Experimental Biology 209, 4371-4378 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02524

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PKC knockout mouse lenses are more susceptible to oxidative stress damage

Dingbo Lin¹, Micheal Barnett¹, Samuel Lobell¹, Daniel Madgwick¹, Denton Shanks¹, Lloyd Willard², Guido A. Zampighi³ and Dolores J. Takemoto^1,*

¹ Department of Biochemistry, Kansas State University, Manhattan, KS 66506, USA
² Department of Diagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506, USA
³ Department of Neurobiology and Jules Stein Eye Institute, David Geffen School of Medicine, Los Angeles, CA90095, USA

^* Author for correspondence (e-mail: dtak{at}ksu.edu)

Accepted 5 September 2006

Cataracts, or lens opacities, are the leading cause of blindness worldwide. Cataracts increase with age and environmental insults, e.g. oxidative stress. Lens homeostasis depends on functional gap junctions. Knockout or missense mutations of lens gap junction proteins, Cx46 or Cx50, result in cataractogenesis in mice. We have previously demonstrated that protein kinase C (PKC) regulates gap junctions in the lens epithelium and cortex. In the current study, we further determined whether PKC control of gap junctions protects the lens from cataractogenesis induced by oxidative stress in vitro, using PKC knockout and control mice as our models. The results demonstrate that PKC knockout lenses are normal at 2 days post-natal when compared to control. However, cell damage, but not obvious cataract, was observed in the lenses of 6-week-old PKC knockout mice, suggesting that the deletion of PKC causes lenses to be more susceptible to damage. Furthermore, in vitro incubation or lens oxidative stress treatment by H₂O₂ significantly induced lens opacification (cataract) in the PKC knockout mice when compared to controls. Biochemical and structural results also demonstrated that H₂O₂ activation of endogenous PKC resulted in phosphorylation of Cx50 and subsequent inhibition of gap junctions in the lenses of control mice, but not in the knockout. Deletion of PKC altered the arrangement of gap junctions on the cortical fiber cell surface, and completely abolished the inhibitory effect of H₂O₂ on lens gap junctions. Data suggest that activation of PKC is an important mechanism regulating the closure of the communicating pathway mediated by gap junction channels in lens fiber cells. The absence of this regulatory mechanism in the PKC knockout mice may cause those lenses to have increased susceptibility to oxidative damage.

Key words: oxidative stress, gap junction, cataract, lens, protein kinase C

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