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Impaired Tubular Uptake Explains Albuminuria in Early Diabetic Nephropathy

Leileata M. Russo^*, Ruben M. Sandoval, Silvia B. Campos, Bruce A. Molitoris^,, Wayne D. Comper^,|| and Dennis Brown^*

^* Program in Membrane Biology, Center for Systems Biology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Division of Nephrology, Indiana Center for Biological Microscopy, Indiana University Medical Center, and Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Exosome Diagnostics Inc., New York, New York; and ^|| Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia

Correspondence: Dr. Leileata M. Russo, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital/Harvard Medical School, Simches Research Center, 185 Cambridge Street, Room 8100, Boston, MA 02114. Phone: 617-726-7496; Fax: 617-643-3182; E-mail: leileata.russo{at}receptor.mgh.harvard.edu

Received for publication May 16, 2008. Accepted for publication September 30, 2008.

Understanding the pathogenesis of albuminuria in diabetic nephropathy is important to improve methods for early diagnosis and treatment. In this study, we addressed whether albuminuria in diabetes results from altered glomerular filtration and/or altered processing of filtered albumin by the proximal tubule. Type 1 diabetic Munich Wistar rats developed albuminuria after 12 wk of diabetes. Intravital two-photon microscopy revealed similar glomerular permeability in the diabetic and control animals, assessed using both albumin-Alexa568 and 69-kD FITC-dextran; however, diabetic animals demonstrated significantly less filtered fluorescent albumin in renal proximal tubule (PT) cells compared with control animals. We also observed increased albumin-derived urinary peptide excretion in diabetic animals, and hyperglycemia modulated this peptideuria. In conclusion, in the early stages of diabetic nephropathy, the PT plays a major role in the development of albuminuria, which may be preceded by peptideuria.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673