Augmenting podocyte injury promotes advanced diabetic kidney disease in Akita mice.
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.
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, United States.
Liming
L
Wang
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, United States.
Yuping
Y
Tang
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, United States.
William
W
Eisner
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, United States.
Matthew A
MA
Sparks
Department of Pathology, Duke University Medical Center, Durham, NC 27710, United States.
Anne F
AF
Buckley
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.
Robert F
RF
Spurney
D000419:Albuminuria / Q000150:complications; D000818:Animals; D000963:Antimetabolites / Q000009:adverse effects; D043525:Cytosine Deaminase / Q000235:genetics; D003928:Diabetic Nephropathies / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005437:Flucytosine / Q000009:adverse effects; D005472:Fluorouracil / Q000009:adverse effects; D015870:Gene Expression; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011355:Prodrugs / Q000009:adverse effects
D000963:Antimetabolites; D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil
Diabetes mellitus; Diabetic nephropathy; Podocyte