Augmenting podocyte injury promotes advanced diabetic kidney disease in Akita mice

• Published in: Biochemical and biophysical research communications 2014-02, Vol.444 (4), p.622-627
• Main Authors: Wang, Liming, Tang, Yuping, Eisner, William, Sparks, Matthew A., Buckley, Anne F., Spurney, Robert F.
• Format: Article
• Language: English
• Subjects: Albuminuria - complications; Animals; Antimetabolites - adverse effects; Cytosine Deaminase - genetics; Diabetes mellitus; Diabetic Nephropathies - blood; Diabetic Nephropathies - enzymology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - pathology; Diabetic nephropathy; Disease Models, Animal; Flucytosine - adverse effects; Fluorouracil - adverse effects; Gene Expression; Kidney - drug effects; Kidney - enzymology; Kidney - metabolism; Kidney - pathology; Mice; Podocyte; Podocytes - drug effects; Podocytes - enzymology; Podocytes - metabolism; Podocytes - pathology; Prodrugs - adverse effects
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.01.115

•Augmenting podocyte injury promotes robust albuminuria in diabetic mice.•Podocyte injury causes advanced histologic features of diabetic kidney disease.•Podocyte number correlates inversely with albuminuria and mesangial expansion. 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 4–5week old Akita mice with 5-FC for 5days caused robust albuminuria at 16 and 20weeks of age compared to 5-FC treated Akita controls, which do not express CD (Akita CTLs). By 20weeks 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 20weeks 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.