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 6

Diabetic kidney injury improves in c-MafΔTAM mice through reduced oxidative stress and inflammatory cytokine levels.

Options: View larger image (or click on image) Download as PowerPoint
Diabetic kidney injury improves in c-MafΔTAM mice through reduced oxidat...
Decreased (A and B) PAMS-positive mesangial matrix index and (C and D) Sirius red–positive area indicate the suppression of diabetic kidney injury in c-MafΔTAM mice (A and B: c-Maffl/fl, n = 5; c-MafΔTAM, n = 7. C and D: n = 5 per group). Kidney sections collected on STZ(12w) TAM(8w) were used for both staining procedures. The increased ratio of mesangial matrix and fibrogenesis in c-MafΔTAM mice was ameliorated compared with c-Maffl/fl mice. The mesangial matrix index represents the ratio of the mesangial matrix area (green) to the tuft area (glomerulus in red). Tubulointerstitial fibrogenesis lesions, defined as Sirius red–positive areas (blue), were measured to detect fibrogenesis and expressed as a percentage of the total area. (E) Col1a1, (F) Col4a3, and (G) fibronectin expression on STZ(12w) TAM(8w) (c-Maffl/fl, n = 5; c-MafΔTAM, n = 7). (H) IHC staining of 8-OHdG distribution in the kidneys STZ(12w) TAM(8w) (n = 4 per group). (I) Urinary 8-OHdG levels indicate reduced oxidative stress in the kidneys of c-MafΔTAM mice compared with c-Maffl/fl mice [n = 5 per group on TAM(10d); c-Maffl/fl, n = 5 and c-MafΔTAM, n = 7 on STZ(12w) TAM(8w)]. (J) Tgfβ and (K) Il-6 expression on STZ(12w) TAM(8w) (c-Maffl/fl, n = 5; c-MafΔTAM, n = 7). Scale bars: 100 μm. B, D–G, and I–K 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, **P < 0.01, ***P < 0.001. White circles: c-Maffl/fl groups, and black circles: c-MafΔTAM groups.