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Am J Physiol Renal Physiol (March 15, 2005). doi:10.1152/ajprenal.00351.2004
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Submitted on September 16, 2004
Accepted on March 13, 2005

Ischemia-Induced Cleavage of Cadherins in NRK Cells: Evidence for a Role of Metalloproteinases

Marisa D. Covington1, Kayla J. Bayless2, Robert C. Burghardt3, George E. Davis2, and Alan R. Parrish1*

1 Department of Pharmacology and Toxicology, College of Medicine, Texas A&M University System Health Science Center, College Station, TX, USA
2 Department of Pathology and Laboratory Medicine, College of Medicine, Texas A&M University System Health Science Center, College Station, TX, USA
3 Department of Veterinary Integrated Biosciences, College of Veeterinary Medicine, Texas A&M University, College Station, TX, USA

* To whom correspondence should be addressed. E-mail: Parrish{at}medicine.tamhsc.edu.

Although ischemia has been shown to disrupt cell adhesion, the underlying molecular mechanism is unknown. In these studies, we adapted a model of ischemia/reperfusion to normal rat kidney (NRK) cells, examined disruption of the cadherin/catenin complex, and identified a role for matrix metalloproteinases (MMPs) in ischemia-induced cleavage of cadherins. In NRK cells, ischemia was induced by applying a thin layer of phosphate buffered saline (PBS) solution supplemented with calcium and magnesium and a layer of mineral oil, which restricts exposure to oxygen. NRK cells exhibited an extracellular 80 kDa and intracellular 40 kDa E-cadherin fragments after 4 hr of ischemia, and at 6 hr the expression of full length E-cadherin decreased. While no fragments of N-cadherin, {alpha}-catenin, and {gamma}-catenin were observed at any time point, the detectable levels of these proteins decreased during ischemia. Ischemia was detected by an increase in pimonidazole adducts, as well as an increase in glucose transporter-1 (GLUT-1) protein expression. Ischemia did not decrease cell number, but there was a decrease in ATP levels. In addition, there was no evidence of cleaved caspase 3 or 9 during 6 hr of ischemia. The MMP inhibitors, GM6001 and TAPI-O, inhibited cleavage and/or loss of E- and N-cadherin protein expression. TIMP-3 and to a lesser extent TIMP-2, but not TIMP-1, inhibits ischemic cleavage and/or loss of E- and N-cadherin. These results demonstrate that ischemia induces a selective metalloproteinase-dependent cleavage of E-cadherin and decrease in N-cadherin that is associated with a disruption of junctional contacts.




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