RESUMEN
BACKGROUND: Diabetic nephropathy (DN) is a life-threatening renal disease and needs urgent therapies. Wogonin is renoprotective in DN. This study aimed to explore the mechanism of how wogonin regulated high glucose (HG)-induced renal cell injury. METHODS: Diabetic mice (db/db), control db/m mice, and normal glucose (NG)- or HG-treated human tubule epithelial cells (HK-2) were used to evaluate the levels of suppressor of cytokine signaling 3 (SOCS3), Toll-like receptor 4 (TLR4), inflammation and fibrosis. Lentivirus was used to regulate SOCS3 and TLR4 expressions. After oral gavage of wogonin (10 mg/kg) or vehicle in db/db mice, histological morphologies, blood glucose, urinary protein, serum creatinine values (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione (GSH), and reactive oxygen species (ROS) were assessed. RT-qPCR and Western blot evaluated inflammation and fibrosis-related molecules. RESULTS: HG exposure induced high blood glucose, severe renal injuries, high serumal Src and BUN, low SOD and GSH, and increased ROS. HG downregulated SOCS3 but upregulated TLR4 and JAK/STAT, fibrosis, and inflammasome-related proteins. Wogonin alleviated HG-induced renal injuries by decreasing cytokines, ROS, Src, and MDA and increasing SOD and GSH. Meanwhile, wogonin upregulated SOCS3 and downregulated TLR4 under HG conditions. Wogonin-induced SOCS3 overexpression directly decreased TLR4 levels and attenuated JAK/STAT signaling pathway-related inflammation and fibrosis, but SOCS3 knockdown significantly antagonized the protective effects of wogonin. However, TLR4 knockdown diminished SOCS3 knockdown-induced renal injuries. CONCLUSION: Wogonin attenuates renal inflammation and fibrosis by upregulating SOCS3 to inhibit TLR4 and JAK/STAT pathway.
Asunto(s)
Nefropatías Diabéticas , Flavanonas , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas , Receptor Toll-Like 4 , Flavanonas/farmacología , Flavanonas/uso terapéutico , Receptor Toll-Like 4/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/etiología , Animales , Transducción de Señal/efectos de los fármacos , Ratones , Humanos , Masculino , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Línea Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
The development of acute kidney injury (AKI) is a complex process involving tubular, inflammatory, and vascular components, but less is known about the role of the interstitial microenvironment. We have previously shown that the extracellular matrix glycoprotein tenascin-C (TNC) is induced in fibrotic kidneys. In mouse models of AKI induced by ischemia-reperfusion injury (IRI) or cisplatin, TNC was induced de novo in the injured sites and localized to the renal interstitium. The circulating level of TNC protein was also elevated in AKI patients after cardiac surgery. Knockdown of TNC by shRNA in vivo aggravated AKI after ischemic or toxic injury. This effect was associated with reduced renal ß-catenin expression, suggesting an impact on Wnt signaling. In vitro, TNC protected tubular epithelial cells against apoptosis and augmented Wnt1-mediated ß-catenin activation. Co-immunoprecipitation revealed that TNC physically interacts with Wnt ligands. Furthermore, a TNC-enriched kidney tissue scaffold prepared from IRI mice was able to recruit and concentrate Wnt ligands from the surrounding milieu ex vivo. The ability to recruit Wnt ligands in this ex vivo model diminished after TNC depletion. These studies indicate that TNC is specifically induced at sites of injury and recruits Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after AKI.
Asunto(s)
Lesión Renal Aguda/patología , Tenascina/metabolismo , Vía de Señalización Wnt , Lesión Renal Aguda/sangre , Lesión Renal Aguda/etiología , Adulto , Animales , Apoptosis , Línea Celular , Cisplatino/toxicidad , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/patología , Matriz Extracelular/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Voluntarios Sanos , Humanos , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/patología , Ligandos , Masculino , Ratones , Persona de Mediana Edad , ARN Interferente Pequeño/metabolismo , Regeneración , Daño por Reperfusión/complicaciones , Tenascina/sangre , Tenascina/genética , Proteína Wnt1/metabolismoRESUMEN
BACKGROUND: Fabry disease is a kind of lysosomal storage disease resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A (GLA). A mutation in the GLA gene leads to a loss of activity of alpha-galactosidase A. Some drugs, such as hydroxychloroquine, can cause pathological changes similar to those usually seen in Fabry disease. CASE SUMMARY: We report the case of a 41-year-old female patient who was diagnosed with undifferentiated connective tissue disease in 2008. Hydroxychloroquine treatment started 2 years ago, and proteinuria and hematuria increased. Renal biopsy demonstrated renal phospholipidosis. Zebra bodies and myelin figures were found by renal electron microscopy and were initially thought to be indicators of Fabry disease. A genetic analysis of the patient and her family members did not reveal mutations in the GLA gene, supporting a diagnosis of hydroxychloroquine-induced renal phospholipidosis. CONCLUSION: This report reveals one of the adverse effects of hydroxychloroquine. We should pay more attention to hydroxychloroquine-induced renal phospholipidosis.