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Biochem Biophys Res Commun. 2014 Feb 21;444(4):622-7. doi: 10.1016/j.bbrc.2014.01.115. Epub 2014 Jan 31.

Augmenting podocyte injury promotes advanced diabetic kidney disease in Akita mice.

Author information

1
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, United States.
2
Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States.
3
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, United States. Electronic address: robert.spurney@dm.duke.edu.

Abstract

To determine if augmenting podocyte injury promotes the development of advanced diabetic nephropathy (DN), we created mice that expressed the enzyme cytosine deaminase (CD) specifically in podocytes of diabetic Akita mice (Akita-CD mice). In these mice, treatment with the prodrug 5-flucytosine (5-FC) causes podocyte injury as a result of conversion to the toxic metabolite 5-fluorouracil (5-FU). We found that treatment of 4-5 week old Akita mice with 5-FC for 5 days caused robust albuminuria at 16 and 20 weeks of age compared to 5-FC treated Akita controls, which do not express CD (Akita CTLs). By 20 weeks of age, there was a significant increase in mesangial expansion in Akita-CD mice compared to Akita CTLs, which was associated with a variable increase in glomerular basement membrane (GBM) width and interstitial fibrosis. At 20 weeks of age, podocyte number was similarly reduced in both groups of Akita mice, and was inversely correlated with the albuminuria and mesangial expansion. Thus, enhancing podocyte injury early in the disease process promotes the development of prominent mesangial expansion, interstitial fibrosis, increased GBM thickness and robust albuminuria. These data suggest that podocytes play a key role in the development of advanced features of diabetic kidney disease.

KEYWORDS:

Diabetes mellitus; Diabetic nephropathy; Podocyte

PMID:
24491571
PMCID:
PMC3985087
DOI:
10.1016/j.bbrc.2014.01.115
[Indexed for MEDLINE]
Free PMC Article

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