Synergism between phospholipase D2 and sorbitol accumulation in diabetic cataract formation through modulation of Na,K-ATPase activity and osmotic stress.
Phospholipase D (PLD), a highly regulated enzyme that generates the second messenger phosphatidic acid, functions in signal transduction, membrane trafficking and cytoskeletal reorganization. PLD is thought to be involved in the pathogenesis of diabetic complications by activating PKC. Since PKC and PLD are present in the lens we sought to determine if PLD plays a role in diabetic cataract development. We developed transgenic mice that overexpress PLD2, one of the two mammalian isoforms of PLD. These mice developed congenital nuclear cataracts, but not diabetic cataracts. Histological analysis revealed vacuole formation in the fiber cells, mediated potentially by the substantially increased Na,K-ATPase activity. In the presence of the aldose reductase overexpressing transgene that increases lens osmotic pressure, these double transgenic mice developed more severe congenital cataract and became susceptible to develop diabetic cataract. Together, these data suggest that increased PLD2 activity in the lens under hyperglycemic condition might impair its osmoregulatory mechanism and reduce its ability to cope with the osmotic stress triggered by sorbitol accumulation.
Huang
Ping
P
Institute of Molecular Biology, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China.
Jiang
Zhirong
Z
Teng
Shuzhi
S
Wong
Y C
YC
Frohman
Michael A
MA
Chung
Sookja K
SK
Chung
Stephen S M
SS
D000818:Animals; D002386:Cataract / Q000151:congenital / Q000209:etiology / Q000378:metabolism*; D048909:Diabetes Complications / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D018450:Disease Progression; D004198:Disease Susceptibility; D015870:Gene Expression; D051379:Mice; D008822:Mice, Transgenic; D009995:Osmosis; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism*
D013012:Sorbitol; C105606:phospholipase D2; D010739:Phospholipase D; D000254:Sodium-Potassium-Exchanging ATPase