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.
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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

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Figure 5

c-Maf loss attenuates diabetic conditions.

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c-Maf loss attenuates diabetic conditions. (A) c-MafΔTAM mice (n = 11) ...
(A) c-MafΔTAM mice (n = 11) displayed significantly lower blood glucose levels after 10-hour fasting than c-Maffl/fl mice (B) but no significant difference in glucose intolerance between 2 groups. n = 6 on STZ(9w) TAM(5w). (C) Creatinine clearance rate, (D) osmolar clearance, and (E) urine volume were reduced in c-MafΔTAM mice, as a result of improved glomerular hyperfiltration, compared with control mice. [C: n = 5 per group on TAM(10d); c-Maffl/fl, n = 5 and c-MafΔTAM, n = 7 on STZ(12w). D: n = 5 per group on TAM(10d); c-Maffl/fl, n = 4 and c-MafΔTAM, n = 7 on STZ(12w). E: n = 6 per group on STZ(3w) TAM(-1w); c-Maffl/fl, n = 5 and c-MafΔTAM, n = 7 on STZ(12w) TAM(8w)]. Different mice were assessed on TAM(10d) and STZ(12w) TAM(8w). c-Maf deletion attenuated diabetic kidney nephropathy, as indicated by an improvement in (F) serum creatinine and (G) serum UN levels in c-MafΔTAM mice compared with c-Maffl/fl mice, as well as (H) urinary albumin levels on TAM(10d) (left) and STZ(12w) TAM(8w) (center) and glomerular urinary albumin levels on STZ(12w) TAM(8w) (right). [F and G: n = 5 per group on TAM(10d); c-Maffl/fl, n = 5 and c-MafΔTAM, n = 6 on STZ(12w). H: n = 8 per group on TAM(10d); c-Maffl/fl, n = 5 and c-MafΔTAM, n = 6 on STZ(12w)]. B–H 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. Holm-Šídák corrections were applied for multiple statistical tests in A. *P < 0.05, **P < 0.01, ***P < 0.001. White circles: c-Maffl/fl groups, and black circles: c-MafΔTAM groups.