The amount of
albumin filtered through the glomeruli and reabsorbed at the proximal tubules in normal and in diabetic kidneys is debated. The
megalin/
cubilin complex mediates
protein reabsorption, but genetic knockout of
megalin is perinatally lethal. To overcome current technical problems, we generated a drug-inducible
megalin-knockout mouse line,
megalin(lox/lox);Ndrg1-CreERT2 (iMegKO), in which
megalin expression can be shut off at any time by administration of
tamoxifen (Tam). Tam administration in adult iMegKO mice decreased the expression of renal
megalin protein by 92% compared with that in wild-type C57BL/6J mice and almost completely abrogated renal reabsorption of intravenously injected
retinol-binding protein. Furthermore, urinary
albumin excretion increased to 175 μg/d (0.46 mg
albumin/mg
creatinine) in Tam-treated iMegKO mice, suggesting that this was the amount of total nephron
albumin filtration. By comparing Tam-treated,
streptozotocin-induced diabetic iMegKO mice with Tam-treated nondiabetic iMegKO mice, we estimated that the development of diabetes led to a 1.9-fold increase in total nephron
albumin filtration, a 1.8-fold increase in reabsorption, and a significant reduction in reabsorption efficiency (86% efficiency versus 96% efficiency in nondiabetic mice).
Insulin treatment normalized these abnormalities. Akita;iMegKO mice, another model of
type 1 diabetes, showed equivalent results. Finally, nondiabetic iMegKO mice had a glomerular sieving coefficient of
albumin of 1.7×10-5, which approximately doubled in diabetic iMegKO mice. This study reveals actual values and changes of
albumin filtration and reabsorption in early
diabetic nephropathy in mice, bringing new insights to our understanding of renal
albumin dynamics associated with the hyperfiltration status of
diabetic nephropathy.