Impaired Albumin Uptake and Processing Promote Albuminuria in OVE26 Diabetic Mice

Abstract

The importance of proximal tubules dysfunction to diabetic albuminuria is uncertain. OVE26 mice have the most severe albuminuria of all diabetic mouse models but it is not known if impaired tubule uptake and processing are contributing factors. In the current study fluorescent albumin was used to follow the fate of albumin in OVE26 and normal mice. Compared to normal urine, OVE26 urine contained at least 23 times more intact fluorescent albumin but only 3-fold more 70 kD fluorescent dextran. This indicated that a function other than size selective glomerular sieving contributed to OVE26 albuminuria. Imaging of albumin was similar in normal and diabetic tubules for 3 hrs after injection. However 3 days after injection a subset of OVE26 tubules retained strong albumin fluorescence, which was never observed in normal mice. OVE26 tubules with prolonged retention of injected albumin lost the capacity to take up albumin and there was a significant correlation between tubules unable to eliminate fluorescent albumin and total albuminuria. TUNEL staining revealed a 76-fold increase in cell death in OVE26 tubules that retained fluorescent albumin. These results indicate that failure to process and dispose of internalized albumin leads to impaired albumin uptake, increased albuminuria, and tubule cell apoptosis.

Acute Hyperglycemia May Induce Renal Tubular Injury Through Mitophagy Inhibition

“…Urinary microalbumin (UMA), a traditional marker representing damages of glomerular filtration barrier and glomerular hyperfiltration, increased gradually in a dosedependent manner since blood glucose reached 11.1 mmol/L. In recent years, UMA is believed to be primarily controlled by renal tubular epithelial cells, which represents tubular reabsorption dysfunction defined as "diabetic tubulopathy" (22)(23)(24). A good correlation was found between urinary albumin excretion and markers of tubular dysfunction.…”

A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli

“… 10 Increased Ps’alb was measured in glomeruli isolated from diabetic rats, even in those with mild proteinuria, suggesting that the assay is sensitive to early changes in renal function Albuminuria can be impacted by tubular reuptake of albumin resulting in variable urinary albumin-to-creatinine ratio values in experimental diabetic models. 35 When tubular reuptake of albumin was inhibited using an inducible transgenic megalin knockout mouse line, this resulted in a 10-fold increase in urinary albumin secretion in diabetic mice. 36 Because our Ps’alb assay measures albumin permeability directly, it circumvents this potential confounding factor and confirms that glomeruli are a target in diabetic kidney disease.…”

Endocytosis of Albumin Induces Matrix Metalloproteinase-9 by Activating the ERK Signaling Pathway in Renal Tubule Epithelial Cells

“…Moreover, Mori et al found that reabsorption of endogenous albumin was doubled in STZ-induced or Akita-inherited type 1 diabetic mice and reabsorption efficiency was reduced at the same time [ 30 ]. Protein accumulation may occur because of an increase in reabsorption or an insufficient ability to process and dispose of internalized protein by proximal tubule cells [ 31 ]. Further studies are warranted to determine whether albumin accumulation in diabetic rat tubules is due to enhanced albumin uptake or a failure to clear internalized albumin.…”