RESUMO
Cantu syndrome is an autosomal dominant disorder, first described by Cantu in 1982, that is characterized by congenital hypertrichosis, characteristic facial anomalies and cardiomegaly. Recent investigations have revealed that this syndrome is caused by mutations of ABCC9, which encodes a regulatory subunit of SUR2, an adenosine triphosphate-mediated potassium channel opener, expressed not only in smooth muscle but also in hair follicles. However, the abnormalities of skin and hair in patients with Cantu syndrome have not been well explored. We herein report three Japanese patients with Cantu syndrome and describe their specific skin manifestations and alterations in the histopathology of their hair follicles and sebaceous glands. Similar alterations were shared among those three patients and may be related to the function of SUR2, namely the regulation of hair follicle growth, because SUR2 is a known pharmacological target of minoxidil.
Assuntos
Cardiomegalia/patologia , Folículo Piloso/patologia , Hipertricose/patologia , Osteocondrodisplasias/patologia , Glândulas Sebáceas/patologia , Anti-Hipertensivos/efeitos adversos , Biópsia , Cardiomegalia/genética , Criança , Pré-Escolar , Feminino , Hirsutismo/induzido quimicamente , Humanos , Hipertricose/genética , Masculino , Minoxidil/efeitos adversos , Mutação , Osteocondrodisplasias/genética , Receptores de Sulfonilureias/genéticaRESUMO
IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL-36α, IL-36ß, and IL-36γ, all of which bind to a heterodimer containing the IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. Therefore, we evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury model of AKI using IL-36R knockout and wild-type mice. IL-36R was found to be expressed in the kidney, mainly in proximal tubules. In IL-36R knockout mice, plasma creatinine, blood urea nitrogen, and IL-6 levels after ischemia-reperfusion injury were significantly lower than those in wild-type mice. Immunohistological analysis revealed mild tubular injury. IL-36α/ß/γ levels were increased after ischemia-reperfusion injury, and IL-36α was expressed in lymphocytes and proximal tubular cells, but post-ischemia-reperfusion injury mRNA levels of IL-6 and TNF-α were low in IL-36R knockout mice. In primary cultures of renal tubular epithelial cells, IL-36α treatment upregulated NF-κB activity and Erk phosphorylation. Notably, in patients with AKI, urine IL-36α levels were increased, and IL-36α staining in renal biopsy samples was enhanced. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI.
Assuntos
Injúria Renal Aguda/prevenção & controle , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Receptores de Interleucina-1/deficiência , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Células Cultivadas , Citocinas/genética , Modelos Animais de Doenças , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Predisposição Genética para Doença , Humanos , Interleucina-1/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Fenótipo , Fosforilação , Receptores de Interleucina-1/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de SinaisAssuntos
Albinismo Oculocutâneo/genética , Idoso , Antígenos de Neoplasias/genética , Povo Asiático/genética , Pré-Escolar , Feminino , Humanos , Lactente , Japão , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Monofenol Mono-Oxigenase/genética , Mutação de Sentido Incorreto , Oxirredutases/genéticaRESUMO
BACKGROUND: Raf is one of the downstream effectors of Ras GTPases, and plays a key role in regulating cell proliferation and differentiation through the activation of MAPK. We have previously demonstrated that temporal induction of Raf in the epidermis of K14-Raf:ER transgenic mice results in epidermal hyperplasia resembling squamous cell carcinoma and psoriasis. It has been demonstrated that epidermal Stat3 activation is required for psoriasis development, since keratinocyte-specific Stat3 activation in a mouse model elicits a psoriasis-like phenotype, which is reversed by inhibition of Stat3 signaling. OBJECTIVE: The aim of this study was whether Stat3 signaling is involved in Raf-MAPK-dependent epidermal hyperplasia. METHODS: K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor ligand binding domain-Raf fusion gene is expressed under control of the keratin 14 promoter, were mated with epidermis-specific Stat3 null mice (K5-Cre.Stat3(flox/flox)). K5-Cre.Stat3(flox/flox) mice were used to define the impact of Stat3 deficiency on Raf-induced epidermal hyperplasia. RESULTS: Over-expression of Raf by 4OHT treatment in K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice greatly attenuated the epidermal hyperplasia and dermal cell infiltrates compared with K14-Raf:ER;K5-Cre.Stat3(flox/WT) mice. Also, up-regulation of psoriasis-associated cytokine profiles, including VEGF, was inhibited in the skin from K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice following 4OHT treatment. CONCLUSION: These results clearly indicate that Raf-MAPK-dependent psoriatic-like epidermal hyperplasia requires Stat3 signaling in keratinocytes.