Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2
Mitsunori Fujino, … , Kunihiro Yamagata, Satoru Takahashi
Mitsunori Fujino, … , Kunihiro Yamagata, Satoru Takahashi
Published February 14, 2023
Citation Information: JCI Insight. 2023;8(6):e163306. https://doi.org/10.1172/jci.insight.163306.
View: Text | PDF
Research Article Nephrology

Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2

Abstract

The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of c-Maf in adult kidneys remain unknown as c-Maf–null C57BL/6J mice exhibit embryonic lethality. In this study, we investigated the role of c-Maf in adult mouse kidneys by comparing the phenotypes of tamoxifen-inducible (TAM-inducible) c-Maf–knockout mice (c-Maffl/fl; CAG-Cre-ERTM mice named “c-MafΔTAM”) with those of c-Maffl/fl control mice, 10 days after TAM injection [TAM(10d)]. In addition, we examined the effects of c-Maf deletion on diabetic conditions by injecting the mice with streptozotocin, 4 weeks before TAM injection. c-MafΔTAM mice displayed primary glycosuria caused by sodium-glucose cotransporter 2 (Sglt2) and glucose transporter 2 (Glut2) downregulation in the kidneys without diabetes, as well as morphological changes and life-threatening injuries in the kidneys on TAM(10d). Under diabetic conditions, c-Maf deletion promoted recovery from hyperglycemia and suppressed albuminuria and diabetic nephropathy by causing similar effects as did Sglt2 knockout and SGLT2 inhibitors. In addition to demonstrating the potentially unique gene regulation of c-Maf, these findings highlight the renoprotective effects of c-Maf deficiency under diabetic conditions and suggest that c-Maf could be a novel therapeutic target gene for treating diabetic nephropathy.

Authors

Mitsunori Fujino, Naoki Morito, Takuto Hayashi, Masami Ojima, Shun Ishibashi, Akihiro Kuno, Seizo Koshiba, Kunihiro Yamagata, Satoru Takahashi

×

Figure 2

RNA-Seq analysis of the relationship between c-Maf and renal features.

Options: View larger image (or click on image) Download as PowerPoint
RNA-Seq analysis of the relationship between c-Maf and renal features. (...
(A) Volcano plot of overall gene expression: 261 genes were upregulated (red) and 113 genes were downregulated (blue) in c-MafΔTAM mice. (B) Top 10 pathways of the DEGs in c-MafΔTAM mice. (C) Heatmap of the expression of 123 genes related to SLC-mediated transmembrane transport between c-MafΔTAM and c-Maffl/fl mice (n = 4 per group). (D) Megalin and (E) cubilin gene expression levels were lower in c-MafΔTAM mice than in c-Maffl/fl mice (n = 10 per group). (F) A tendency for decreased megalin protein expression levels in c-MafΔTAM mice than in c-Maffl/fl mice (n = 4 per group). Scale bars: 100 μm. For RNA-Seq transcriptome analysis, gene expression values were calculated using the quantile method. Gene expression was compared between c-Maffl/fl control mice and c-MafΔTAM mice using the Empirical Analysis DGE tool (edgeR test) in the CLC Genomics Workbench (Version 10.1.1; QIAGEN). False discovery rate (FDR) adjustments (81) were applied to correct for multiple testing, and DEGs were identified using an FDR cutoff of 0.05. D and E were presented as the mean and the standard error of the mean (SEM). To assess whether differences between c-MafΔTAM and c-Maffl/fl mice were statistically significant, a minimum of 3 biological replicates were analyzed using Welch’s t test, and a P value < 0.05 was considered significant. *P < 0.05, and ***P < 0.001. White circles: c-Maffl/fl groups, and black circles: c-MafΔTAM groups.