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Diabetes Publish Ahead of Print published online ahead of print May 16, 2007
DOI: 10.2337/db06-1198
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Original Research

Hyperglycemia Is a Major Determinant of Albumin Permeability In The Diabetic Microcirculation: The Role of µ-Calpain

Rosario Scalia1, Yulan Gong1, Brett Berzins1, Li Juan Zhao1, and Kumar Sharma2

1Department of Physiology, Jefferson Medical College
2Center for Novel Therapies for Kidney Disease, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107

Correspondence: rosario.scalia{at}jefferson.edu

Increased permeability to albumin is a well-known feature of the diabetic microvasculature and a negative prognostic factor of vascular complications. The mechanisms responsible for loss of physiological albumin barrier in diabetic organs remain only partially understood. We have recently demonstrated that the protease µ-calpain is activated in hyperglycemia causing endothelial dysfunction and vascular inflammation. In the present study, we investigated whether µ-calpain is involved in the hyperpermeability of the diabetic vasculature. We also investigated the mechanistic roles of hyperglycemia and leukocyte adhesion in this process. Albumin permeability in the intact microcirculation of the Zucker Diabetic Fatty (ZDF) rat was quantified by intravital microscopy. Extravasation of albumin in the microcirculation of ZDF rats was significantly increased when compared to nondiabetic Zucker Lean (ZL) rats. Microvascular albumin leakage was prevented by either antisense depletion of µ-calpain or pharmacological inhibition of calpain in vivo. Calpain inhibition also attenuated urinary albumin excretion in ZDF rats. Glucose concentrations in the range of those found in the blood of ZDF rats increased albumin permeability in nondiabetic ZL rats, thus demonstrating a mechanistic role for hyperglycemia in the hypermeability of diabetes. Depletion of polymorphonuclear leukocytes in vivo failed to prevent glucose-induced hypermeability, suggesting that hyperglycemia can disrupt the physiological endothelial cell barrier of the microcirculation even in the absence of increased leukocyte-endothelium interactions.


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Copyright © 2007 by the American Diabetes Association.