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. Podocyte-specific 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.

Anaemia is a common complication of patients with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. Nevertheless, the cause and degree of such cases of anaemia have not been elucidated in detail. We aimed to investigate the prevalence, cause, pathogenesis of anaemia and the impact of anaemia on prognosis in patients with ANCA-associated renal vasculitis. We identified 45 patients with ANCA-associated renal vasculitis that were clinically and/or histologically diagnosed and treated from 2003 to 2014 at University of Tsukuba Hospital. The relationships between anaemia and various clinicopathological findings were evaluated. At the time of diagnosis of ANCA-associated renal vasculitis, all patients showed anaemia, with a mean haemoglobin level of 7.5 ± 1.3 g/dL. Renal anaemia was diagnosed in 92% of patients, anaemia of chronic disease (ACD) in 56%, and anaemia due to hemorrhage in 20%. Next, the patients were divided into two groups according to anaemia severity: minimum haemoglobin (min Hb) < 7.5 (n = 24) and min Hb ≥ 7.5 (n = 21). A comparison of baseline characteristics showed that serum albumin, maximum serum creatinine, minimum estimated glomerular filtration rate (eGFR), serum cystatin C, and the area of tubulointerstitial damage were significantly different between the haemoglobin groups (p < 0.05). No significant intergroup differences were observed in iron-related or inflammation-related data. With regard to the relationship between anaemia severity and prognosis, patients in the min Hb < 7.5 group tended to have a lower eGFR. Anaemia severity was associated with markedly lower survival (Log-rank test, p = 0.03). In this cohort of patients with ANCA-associated renal vasculitis, all subjects exhibited anaemia. In regard to the cause and pathogenesis, the most prevalent form of anaemia was renal anaemia, not ACD, and a potential reason for the high prevalence of anaemia in our cohort may have been the interaction between renal anaemia and ACD. Moreover, anaemia severity was significantly associated with the degree of renal dysfunction and life prognosis.

Monocytes and macrophages express the transcription factor MAFB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B) and protect against ischemic acute kidney injury (AKI). However, the mechanism through which MAFB alleviates AKI in macrophages remains unclear. In this study, we induced AKI in macrophage lineage-specific Mafb-deficient mice (C57BL/6J) using the ischemia-reperfusion injury model to analyze these mechanisms. Our results showed that MAFB regulates the expression of Alox15 (arachidonate 15-lipoxygenase) in macrophages during ischemic AKI. The expression of ALOX15 was significantly decreased at the mRNA and protein levels in macrophages that infiltrated the kidneys of macrophage-specific Mafb-deficient mice at 24 h after ischemia-reperfusion injury. ALOX15 promotes the resolution of inflammation under acute conditions by producing specialized proresolving mediators by oxidizing essential fatty acids. Therefore, MAFB in macrophages promotes the resolution of inflammation in ischemic AKI by regulating the expression of Alox15. Moreover, MAFB expression in macrophages is upregulated via the COX-2/PGE2/EP4 pathway in ischemic AKI. Our in vitro assay showed that MAFB regulates the expression of Alox15 under the COX-2/PGE2/EP4 pathway in macrophages. PGE2 mediates the lipid mediator (LM) class switch from inflammatory LMs to specialized proresolving mediators. Therefore, MAFB plays a key role in the PGE2-mediated LM class switch by regulating the expression of Alox15. Our study identified a previously unknown mechanism by which MAFB in macrophages alleviates ischemic AKI and provides new insights into regulating the LM class switch in acute inflammatory conditions.

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-Maf ^fl/fl ; CAG-Cre-ER ^TM mice named “ c-Maf ^ΔTAM ”) with those of c-Maf ^fl/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-Maf ^ΔTAM 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.

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands.