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 (TAM)-inducible c-Maf knockout mice (c-Maf flox/flox ; CAG-Cre-ER TM mice named "c-Maf ΔTAM ") with that of c-Maf flox/flox 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 (STZ), 4 weeks before TAM injection. c-Maf ΔTAM mice displayed primary glycosuria caused by Sglt2 and 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 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.

Exploring Large MAF Transcription Factors: Functions, Pathology, and Mouse Models with Point Mutations

“…Moreover, the mechanistic roles of c-MAF in the recovery from acute injury in the intestine promote the differentiation of epithelial cells and the importance of crosstalk between differentiated tuft cells and enterocytes to accelerate long-term intestinal accommodation [21]. While these two studies suggested a requirement for c-MAF in organ injury, we report a protective effect of c-MAF deficiency against diabetes and diabetes-induced nephropathy through c-MAF regulation of the glucose transporters SGLT2 and GLUT2, which are expressed in the proximal tubules of kidneys [22]. In summary, c-MAF deficiency is interesting and has the potential to decrease susceptibility and provide protection against injury and diseases.…”

“…Subsequently, other st have demonstrated inhibition of the development of the liver sinusoid by specific de of c-MAF in endothelial cells, which induces aberrant expansion of postnatal liver h topoiesis, accelerates excessive proliferation of sinusoidal cells during the postnat riod, and worsens sensitivity of pro-fibrotic effects in the liver to chemical insults Moreover, the mechanistic roles of c-MAF in the recovery from acute injury in the inte promote the differentiation of epithelial cells and the importance of crosstalk betwee ferentiated tuft cells and enterocytes to accelerate long-term intestinal accommod [21]. While these two studies suggested a requirement for c-MAF in organ injury, w port a protective effect of c-MAF deficiency against diabetes and diabetes-ind nephropathy through c-MAF regulation of the glucose transporters SGLT2 and GL which are expressed in the proximal tubules of kidneys [22]. In summary, c-MAF ciency is interesting and has the potential to decrease susceptibility and provide p tion against injury and diseases.…”

“…Since c-MAF plays important roles in lens, bone, liver, and kidney formation, and patients with c-MAF mutations show many disorders, such as congenital cataracts, deafness, skeletal dysplasia, dental abnormalities, epilepsy, mental retardation, calcifications of the bilateral putamen nucleus, pericardial effusion, exostosis of the distal phalanx, and femoral neck fracture [21][22][23][24][25], it was considered that MAFB mutations also cause various diseases. Since Mafb homozygous knockout mice die immediately after birth due to respiratory failure, it was thought that Mafb heterozygous mutant patients might have abnormalities in their respiratory organs, followed by several other organs, such as the ears, parathyroid glands, and kidneys, as demonstrated in MAFB-knockout and conditional knockout mice.…”

Sympathetic Activation Promotes Sodium Glucose Co-Transporter-1 Protein Expression in Rodent Skeletal Muscle

“…This suggests that it is likely, that compared to the Sglt1 gene in the skeletal muscle, the DNA for the Sglt2 gene in skeletal muscle may be more tightly wound around it's supporting proteins to form chromatin and this could affect the genes availability for transcription [32]. Additionally, the transcription factors for the Sglt2 gene such as C-Maf [33] may not be present in many tissues which may explain the limited expression of SGLT2 in the body.…”