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J Am Soc Nephrol. 2014 Nov;25(11):2546-57. doi: 10.1681/ASN.2013090993. Epub 2014 Apr 10.

Overexpression of Mafb in podocytes protects against diabetic nephropathy.

Author information

1
Departments of Nephrology and morito@md.tsukuba.ac.jp.
2
Departments of Nephrology and.
3
Anatomy and Embryology, Faculty of Medicine.
4
Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Inashiki, Ibaraki, Japan; and.
5
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
6
Anatomy and Embryology, Faculty of Medicine, International Institute for Integrative Sleep Medicine (WPI-IIIS), and Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Ibaraki, Japan;

Abstract

We previously showed that the transcription factor Mafb is essential for podocyte differentiation and foot process formation. Podocytes are susceptible to injury in diabetes, and this injury leads to progression of diabetic nephropathy. In this study, we generated transgenic mice that overexpress Mafb in podocytes using the nephrin promoter/enhancer. To examine a potential pathogenetic role for Mafb in diabetic nephropathy, Mafb transgenic mice were treated with either streptozotocin or saline solution. Diabetic nephropathy was assessed by renal histology and biochemical analyses of urine and serum. Podocyte-specific overexpression of Mafb had no effect on body weight or blood glucose levels in either diabetic or control mice. Notably, albuminuria and changes in BUN levels and renal histology observed in diabetic wild-type animals were ameliorated in diabetic Mafb transgenic mice. Moreover, hyperglycemia-induced downregulation of Nephrin was mitigated in diabetic Mafb transgenic mice, and reporter assay results suggested that Mafb regulates Nephrin directly. Mafb transgenic glomeruli also overexpressed glutathione peroxidase, an antioxidative stress enzyme, and levels of the oxidative stress marker 8-hydroxydeoxyguanosine decreased in the urine of diabetic Mafb transgenic mice. Finally, Notch2 expression increased in diabetic glomeruli, and this effect was enhanced in diabetic Mafb transgenic glomeruli. These data indicate Mafb has a protective role in diabetic nephropathy through regulation of slit diaphragm proteins, antioxidative enzymes, and Notch pathways in podocytes and suggest that Mafb could be a therapeutic target.

PMID:
24722438
PMCID:
PMC4214526
DOI:
10.1681/ASN.2013090993
[Indexed for MEDLINE]
Free PMC Article

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