Acute hyperglycemia induces rapid, reversible increases in glomerular permeability in nondiabetic rats

Abstract

Axelsson J, Rippe A, Rippe B. Acute hyperglycemia induces rapid, reversible increases in glomerular permeability in nondiabetic rats. Am J Physiol Renal Physiol 298: F1306 -F1312, 2010. First published March 17, 2010 doi:10.1152/ajprenal.00710.2009.-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 ϭ 8); 2) hypertonic glucose as in 1) and a RhoA-kinase inhibitor (Y-27632; Rho-G; n ϭ 8); 3) 20% mannitol (MANN; n ϭ 7) or 4) hypertonic (12%) NaCl to maintain plasma crystalloid osmotic pressure (cry) at ϳ320 -325 mosmol/l (NaCl; n ϭ 8) or 5) physiological saline (SHAM; n ϭ 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 () for polydisperse Ficoll (molecular radius 15-80 Å) by highperformance size-exclusion chromatography. In G there was a marked increase in for Ficoll55-80Å 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. microalbuminuria; RhoA-kinase; podocytes; endothelium; hyperosmolarity CHRONIC HYPERGLYCEMIA (HG), such as in diabetes mellitus, may cause macro-and microangiopathy with microalbuminuria as an early sign, and, eventually, widespread end-organ damage. The pathophysiological changes behind HG-induced microvascular dysfunction and organ damage are partly elusive, but include 1) the formation of advanced glycation end products (AGE), 2) an abnormal glucose metabolism via the polyol pathway, 3) an increase in diacylglycerol production, which in turn activates PKC, and 4) increased RhoA-kinase (ROCK) activity (6,8,22,23,28,34). With respect to renal injury, HG-induced hemodynamic alterations leading to hyperfiltration also contribute. The final common step causing vascular dysfunction during HG includes an increase in oxidative stress caused by an increased formation of reactive oxygen species (ROS) and decreased endothelial nitric oxide (NO) production. All these alterations may lead to microalbuminuria.In in vitro studies on cultured endothelial monolayers, acute HG has been shown to produce barrier dysfunction and (reversible) endoth...

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