title: Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy.
abstract: 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.
authors.affiliation: Department of Nephrology and.
authors.forename: Keita P
authors.initials: KP
authors.lastname: Mori
authors.affiliation: Department of Nephrology and.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoi
authors.affiliation: Department of Clinical and Translational Research, Institute for Clinical and Translational Science, Nara Medical University, Nara, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kasahara
authors.affiliation: Department of Nephrology and.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Imamaki
authors.affiliation: Department of Nephrology and.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishii
authors.affiliation: Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takashige
authors.initials: T
authors.lastname: Kuwabara
authors.affiliation: Department of Nephrology and.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koga
authors.affiliation: Department of Nephrology and.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Nephrology and.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Toda
authors.affiliation: Department of Nephrology and.
authors.forename: Shoko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Department of Nephrology and.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Endo
authors.affiliation: TK Project and.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Nephrology and.|TMK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
authors.affiliation: Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.affiliation: TMK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; mori@tmk.med.kyoto-u.ac.jp.|Department of Molecular and Clinical Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; and.|Department of Nephrology and Kidney Research, Shizuoka General Hospital, Shizuoka, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000419:Albuminuria / Q000235:genetics; D000818:Animals; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D000071068:Lipocalin-2 / Q000652:urine; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009399:Nephrons / Q000378:metabolism*; D065608:Renal Reabsorption
chemical_list: D000418:Albumins; D000071068:Lipocalin-2; D026561:Low Density Lipoprotein Receptor-Related Protein-2
keywords: albuminuria; chronic kidney disease; diabetic nephropathy; endocytosis; glomerular hyperfiltration