title: Hyperglycemia is a major determinant of albumin permeability in diabetic microcirculation: the role of mu-calpain.
abstract: Increased permeability to albumin is a well-known feature of diabetic microvasculature and a negative prognostic factor of vascular complications. The mechanisms responsible for loss of the physiological albumin barrier in diabetic organs remain only partially understood. We have recently demonstrated that the protease mu-calpain is activated in hyperglycemia, which causes endothelial dysfunction and vascular inflammation. In the present study, we investigated whether mu-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 with nondiabetic Zucker lean (ZL) rats. Microvascular albumin leakage was prevented by either antisense depletion of mu-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, this demonstrates a mechanistic role for hyperglycemia in the hypermeability of diabetes. Depletion of polymorphonuclear leukocytes in vivo failed to prevent glucose-induced hypermeability, which suggests that hyperglycemia can disrupt the physiological endothelial cell barrier of the microcirculation, even in the absence of increased overt leukocyte-endothelium interactions.
authors: Department of Molecular Physiology and Biophysics, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107-6799, USA. rosario.scalia@jefferson.edu
authors: Rosario
authors: R
authors: Scalia
authors: Yulan
authors: Y
authors: Gong
authors: Brett
authors: B
authors: Berzins
authors: Li Juan
authors: LJ
authors: Zhao
authors: Kumar
authors: K
authors: Sharma
mesh_terms: D000418:Albumins / Q000502:physiology*; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006943:Hyperglycemia / Q000209:etiology / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D014652:Vascular Diseases / Q000209:etiology / Q000503:physiopathology
chemical_list: D000418:Albumins; D004151:Dipeptides; D004791:Enzyme Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; C400241:benzyloxycarbonylleucyl-leucine aldehyde; D002154:Calpain; C449002:mu-calpain