Overexpression of Mafb in Podocytes Protects against Diabetic Nephropathy

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. Podocytespecific 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.

Glomerular development – Shaping the multi-cellular filtration unit

“…In respect to the glomerulus, Mafb KO mice show a quite similar phenotype as Pod1 KO animals, with a severe maturational defect of developing glomeruli and podocytes [145,150]. Interestingly, a more recent study could demonstrate that Mafb overexpression in podocytes ameliorates the course of diabetic nephropathy by stabilization of slit diaphragm molecules like Nephrin, upregulation of antioxidative enzymes and modulation of Notch signaling pathways [151]. These findings might indicate that Mafb-controlled transcriptional networks involve adaptive mechanisms required in disease states.…”

Genome-Wide Analysis of Wilms’ Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms

“…Indeed, MAFB/Kreisler, TCF21/POD1, LMX1B, and the FoxC-class TFs have already been shown to be of relevance in podocytes. [15][16][17][18][19] Frequently, networks of TFs cooperatively control gene expression by binding in TF modules to enhancers. These tissuespecific DNA-regulatory elements are located distally from the TSS.…”

“…Furthermore, previously described enhancers conferring podocyte-specific gene expression and the TFs bound to these enhancers were recapitulated by our ChIPseq data and motif analysis (Supplemental Figure 7). 8,16,19 Reanalysis of previously published WT1 ChIPseq data from embryonic kidneys, where WT1 is expressed in nephron best matching motifs from public databases are shown on the right with a similarity E value. Promoters are enriched in motifs generally found close to TSS (Ets-class TF, E box, GC box, CCAAT box), whereas enhancers harbor motifs for TFs with established significance in podocytes (Fox-class TFs, Lmx1b, Mafb).…”

NeuroD Expression in Podocytes and Interrelationships with Nephrin at Both Nuclear and Cytoplasmic Sites

“…Previous studies have shown that some neuronal TFs are expressed also in podocytes, such as Kreisler (MafB) which is involved in both early central nervous system organization and in kidney development [34], regulating also Nephrin promoter activity [35]. NeuroD, a member of helix-loop-helix (bHLH) transcription factor, is a potent regulator of neuron differentiation and survival both at an early and late stage of the central nervous system (CNS) development [36, 37], and genetic mutations of NeuroD gene are associated with severe abnormalities of many neurological functions [38-40].…”