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.

Potential relationship between eGFR cystatin C /eGFR creatinine ‐ratio and glomerular basement membrane thickness in diabetic kidney disease

“…According to theory, during conditions of glomerular vascular wall thickening, there should be a measurable difference in the eGFR measured using cystatin C and the actual GFR (e.g., as measured by iohexol) under the assumption that their plasma concentrations are determined chiefly by glomerular filtration. In line with our present results, a decreased diffusional clearance of mid‐sized molecules has been found in experimental and clinical studies of DKD (Lubbad et al, 2015 ; Oberbauer et al, 2000 ; Scandling & Myers, 1992 ). There were; however, considerable variations in the eGFR cystatin C /eGFR creatinine ratio in our data indicating that factors other than glomerular filtration may be involved.…”

Potential Relationship Between eGFRcystatin C/eGFRcreatinine-ratio and Glomerular Basement Membrane Thickness in Diabetic Kidney Disease

“…as measured by iohexol) under the assumption that their plasma concentrations are determined chiefly by glomerular filtration. In line with our present results, a decreased diffusional clearance of mid-sized molecules has been found in experimental and clinical studies of diabetic kidney disease 12, 32, 33 . There were however considerable variations in the eGFR cystatin C /eGFR creatinine ratio in our data indicating that factors other than glomerular filtration may be involved.…”

The complexity of kidney disease and diagnosing it – cystatin C, selective glomerular hypofiltration syndromes and proteome regulation

“…In this investigation, the thickness of the glomerular basement membrane was inversely correlated with the eGFR cystatin C /eGFR creatinine -ratio, which is the expected result according to the pore model for glomerular filtration when the pore length is increased [91]. In-line with these findings, previous experimental studies in a rat model of diabetic kidney disease also showed a lower diffusion capacity for polysucrose [92], indicating possible elongation of pores. However, in a similar more recent study, diabetic rats were shown to exhibit a smaller mean small-pore radius compared to control animals indicating shrunken pores [93].…”