Acute hyperglycemia induces rapid, reversible increases in glomerular permeability in nondiabetic rats.
This study was performed to investigate the impact of acute hyperglycemia (HG) on the permeability of the normal glomerular filtration barrier in vivo. In anesthetized Wistar rats (250-280 g), the left ureter was catheterized for urine collection, while simultaneously blood access was achieved. Rats received an intravenous (iv) infusion of either 1) hypertonic glucose to maintain blood glucose at 20-25 mM (G; n = 8); 2) hypertonic glucose as in 1) and a RhoA-kinase inhibitor (Y-27632; Rho-G; n = 8); 3) 20% mannitol (MANN; n = 7) or 4) hypertonic (12%) NaCl to maintain plasma crystalloid osmotic pressure (pi(cry)) at approximately 320-325 mosmol/l (NaCl; n = 8) or 5) physiological saline (SHAM; n = 8). FITC-Ficoll 70/400 was infused iv for at least 20 min before termination of the experiments, and plasma and urine were collected to determine the glomerular sieving coefficients (theta) for polydisperse Ficoll (molecular radius 15-80 A) by high-performance size-exclusion chromatography. In G there was a marked increase in for Ficoll(55-80A) at 20 min, which was completely reversible within 60 min and abrogated by a Rho-kinase (ROCK) inhibitor, while glomerular permeability remained unchanged in MANN and NaCl. In conclusion, acute HG caused rapid, reversible increases in for large Ficolls, not related to the concomitant hyperosmolarity, but sensitive to ROCK inhibition. The changes observed were consistent with the formation of an increased number of large pores in the glomerular filter. The sensitivity of the permeability changes to ROCK inhibition strongly indicates that the cytoskeleton of the cells in the glomerular barrier may be involved in these alterations.
Department of Nephrology, Lund University, Lund, Sweden.
Josefin
J
Axelsson
Anna
A
Rippe
Bengt
B
Rippe
D000208:Acute Disease; D000577:Amides / Q000008:administration & dosage; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002850:Chromatography, Gel; D004195:Disease Models, Animal; D005362:Ficoll / Q000008:administration & dosage / Q000031:analogs & derivatives; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005950:Glucose Solution, Hypertonic / Q000008:administration & dosage; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology; D007262:Infusions, Intravenous; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D008297:Male; D008353:Mannitol / Q000008:administration & dosage; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D009994:Osmolar Concentration; D009997:Osmotic Pressure; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000577:Amides; D001786:Blood Glucose; D005950:Glucose Solution, Hypertonic; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012462:Saline Solution, Hypertonic; C045540:fluorescein 5-isothiocyanate-Ficoll; C108830:Y 27632; D005362:Ficoll; D008353:Mannitol; D054460:rho-Associated Kinases; D016650:Fluorescein-5-isothiocyanate