title: Reduced glomerular size selectivity in late streptozotocin-induced diabetes in rats: application of a distributed two-pore model.
abstract: Microalbuminuria is an early manifestation of diabetic nephropathy. Potential contributors to this condition are reduced glomerular filtration barrier (GFB) size- and charge selectivity, and impaired tubular reabsorption of filtered proteins. However, it was recently reported that no significant alterations in charge selectivity of the GFB occur in early experimental diabetic nephropathy. We here aimed at investigating the functional changes in the GFB in long-term type-1 diabetes in rats, applying a novel distributed two-pore model. We examined glomerular permeability in 15 male Wistar rats with at least 3 months of streptozotocin (STZ)-induced diabetes (blood glucose ∼20 mmol/L) and in age-matched control rats. The changes in glomerular permeability were assessed by determining the glomerular sieving coefficients (θ) for FITC-Ficoll (molecular radius 20-90 Å) using size exclusion HPLC. The values of θ for FITC-Ficoll of radius >50 Å were significantly increased in STZ-diabetic rats compared to age-matched controls (θ for 50-69 Å = 0.001 vs. 0.0002, and θ for 70-90 Å = 0.0007 vs. 0.00006, P < 0.001), while θ for FITC-Ficoll <50 Å tended to be lower in diabetic rats than in controls (θ for 36-49 Å = 0.013 vs. 0.016, ns). According to the distributed two-pore model, there was primarily an increase in macromolecular transport through large pores in the glomerular filter of diabetic rats associated with a loss of small-pore area. Deterioration in the glomerular size selectivity due to an increase in the number and size-spread of large pores, with no changes in the permeability of the small-pore system, represent the major functional changes observed after 3 months of induced experimental diabetes.
authors.affiliation: Department of Surgery, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Loay
authors.initials: L
authors.lastname: Lubbad
authors.affiliation: Department of Nephrology, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Carl M
authors.initials: CM
authors.lastname: Öberg
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Dhanasekaran
authors.affiliation: Department of Physiology, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Nemmar
authors.affiliation: Department of Surgery, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Fayez
authors.initials: F
authors.lastname: Hammad
authors.affiliation: Department of Internal Medicine, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Javed Y
authors.initials: JY
authors.lastname: Pathan
authors.affiliation: Department of Nephrology, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Rippe
authors.affiliation: Department of Internal Medicine, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates Omran.Bakoush@uaeu.ac.ae.
authors.forename: Omran
authors.identifier: http://orcid.org/0000-0003-1447-9836
authors.initials: O
authors.lastname: Bakoush
keywords: Capillary permeability; diabetic nephropathy; fractional clearance; glomerular filtration barrier; macromolecules; proteinuria; sieving coefficient